Aerobic Work Capacity

A aB crystalline Ubiquitously expressed molecular chaperone from the small heat shock protein family. Mutations in this protein are associated with the familial cardiomyopathies. Abnormal Cardiac Electrical Activity ▶ Cardiac Arrhythmias Absorption Movement of a substance into the internal environment of the body by transport through an epithelial membrane. Acceleration Acceleration should not be confused with speed. Acceleration is the rate of change of velocity that allows an athlete to reach maximum speed in the minimum amount of time. Accessory Pathway Accessory pathways (AP) are extra nodal pathways that connect the atrial myocardium to the ventricle across the AV groove. Typical APs usually exhibit rapid, non decremental, anterograde and retrograde conduction, demonstrating delta wave on a standard surface ECG. WPW is defined as PR interval <0.12 s, delta wave and supraventricular tachycardia. Among patients with WPW syndrome, atrioventricular reciprocating tachycardia is the most common arrhythmia, followed by atrial fibrillation. Acclimation Phenotypic adaptive physiological or behavioral changes occurring within an organism, which reduces the strain or enhances endurance of strain caused by experimentally induced stressful changes in particular climatic factors such as ambient temperature in a controlled environment. Cross-References ▶ Cold Acclimatization Accelerometers Accelerometers are electronic motion sensors that consist of piezoresistive or piezoelectric sensors. Motion sensors are probably the oldest tools available to measure body movement or physical activity. They have evolved from mechanical pedometers to electronic uniaxial and triaxial accelerometers. Physiological (or behavioral) changes that occur within an individual’s lifetime that reduce the physiological strain associated with a particular naturally occurring stressful climatic environment. A phenotypic adaption. Cross-References ▶ Cold Frank C. Mooren (ed.), Encyclopedia of Exercise Medicine in Health and Disease, DOI 10.1007/978-3-540-29807-6, Springer-Verlag Berlin Heidelberg 2012 # A Acid–Base Buffering Systems 1 Acid–Base Buffering Systems 0.9 0.8 DIETER BÖNING Sports Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany 0.7 ΔAcid (mol/l) 2 0.6 0.5 0.4 Synonyms 0.3 Stabilization of hydrogen ion activity or concentration 0.2 0.1 Definition pH is the negative decadic logarithm of hydrogen ion (H+) activity in a solution. Water dissociates into equal amounts of H+ and OH , the reaction is neutral (10 7 mol H+ per kg water, pH 7.0 at 25 C, 6.8 at 37 C). Acids (Ac) dissociate to H+ and the negatively charged rest of the acid (Ac ) or conjugate base, bases to OH and the positively charged base rest or conjugate acid. Strong acids or bases dissociate nearly completely. The tendency to dissociate is smaller in weak acids and bases because of the molecular structure and distribution of charges; it is described by the dissociation constant K = ([H+]  [Ac ])/[Ac], pK being the negative logarithm. If pH = pK, the acid is half-dissociated. This can be artificially obtained by mixing one part of a weak acid (e.g., CH3COOH, acetic acid) with one part of its salt with a strong base (e.g., Na+ CH3COO , sodium acetate), since salts are fully dissociated in water. For another set point of pH, the proportion of acid and salt may be changed. When mixing a strong acid with such a solution, part of the added H+ is bound to the conjugate base of the weak acid, thus the increase in [H+] is attenuated, “buffered”. Equal effects, but into the opposite direction, occur when adding a strong base. Buffer capacity b is defined according to Van Slyke (1922) as b ¼ D½baseŠ  DpH 1 ¼ D½acidŠ  DpH 1 The usual unit in biology (often denominated as Slyke) is mmol l 1, because pH is a dimensionless logarithm. b can be measured by titration with strong acids or bases; the slope of the curve is largest at the pK value (maximal value 0.576 mol mol 1) with an effective range at pH = pK  1 (Fig. 1). Under in vivo conditions (pH values between 6.2 and 7.6 at 30–41 C in various tissues), buffers with pK around 7 are most effective. Actual b depends additionally on the concentration of the buffer. Measurements of buffer capacities in an organism can be either performed in vitro in samples (e.g., blood, tissue samples, cell cultures) or in vivo using implanted electrodes 0 5 6 7 pH 8 9 10 Acid–Base Buffering Systems. Fig. 1 Change of pH in a solution of weak acid (1 mol l 1) with a pK value of 7.0 by addition of strong acid. The dissociation of the pure weak acid is about 1% (pH = 9). Against convention, the y-axis is used for the independent quantity DAcid to demonstrate buffer capacity as slope of the curve (multiplied by 1) or indirect methods like nuclear magnetic resonance. The total amount of bound H+ is calculable as b  DpH. In biology, the meaning of buffering has to be extended: besides physicochemical buffering (described above) respiration (excretion of the volatile acid H2CO3), metabolic effects (consumption or production of nonvolatile acids) and transmembrane fluxes of H+ or corresponding molecules like HCO3 play an important role for pH stability and are considered as special forms of buffering. When evaluating titrations, the different components cannot always be discerned. On a long term also excretion of acid or base by kidney, gut, and sweat glands plays a role. Since hydrogen ions produced in large amounts by metabolism (especially as carbonic and lactic acid) take part in many chemical reactions and influence the charges and thus the conformation of proteins, stabilization of their concentration by the above-mentioned mechanisms is essential for the organism. Basic Mechanisms Physicochemical Buffering In the body, two general types of physicochemical buffers exist: non-bicarbonate (nb) and bicarbonate (b) buffers. Non-bicarbonate Buffers The second dissociation constant of inorganic phosphoric acid (H3PO4 <–> H2PO4 + H+<–> HPO42 + 2H+<–> PO43 + 3H+) fits to the physiological pH range Acid–Base Buffering Systems (pK2 = 6.84 at 37 C), the concentration varying between 1 (extracellular fluid) and 13 (muscle cell water) mmol l 1 at rest. The amount of organic phosphates (creatine phosphate, glucose phosphates, adenosine phosphates, nucleic acids, phospholipids, etc.) is larger especially within cells, but because of the repelling forces among neighboring charges, often dissociation is complete at physiological pH. ATP looses its buffering power by complexing with Mg++ and proteins. This group of buffers may therefore change their buffer effect markedly and rapidly, if phosphate groups are transposed or liberated. Most carboxyl and NH3+ groups in proteinic amino acids possess pK values outside of the pH range in the body or disappear by peptide formation. Only histidine (imidazole group) and to a lower extent cystein (SH group) are effective buffers (pK approximately 6 and 8, respectively, in the free amino acids). Their dissociation varies if neighboring charged groups move as a result of allosteric effects. Best known is the increase of pK values in hemoglobin with deoxygenation. In muscle, histidine is found mainly in proteins (between 15 and 37 mmol l 1) and the dipeptide carnosine (pK = 6.83, 2.5–3.5 mmol l 1), with highest levels in sprinters [4]. A Metabolic Effects Splitting of creatine phosphate (CrP) for production of ATP finally yields inorganic phosphate, thus increasing the amount of nb buffers. Consumption of lactic acid by aerobic metabolism, for example, in the heart or slowtwitch skeletal muscle fibers or by resynthesis of glucose in the liver is an effective means to reduce the acid load. Transmembrane Fluxes of H+ or Corresponding Molecules There are a lot of transporters allowing excretion from cells to the extracellular space or into the opposite direction. Excretion by kidney or sweat glands reduces the acid load of the body; in the case of substances like lactic acid this means a loss of energy and seems not to play a significant role. Movement between body compartments is only helpful, if a more sensitive tissue (e.g., the brain) has to be protected by shifting H+ into cells with high physicochemical buffer capacity as observed during severe respiratory acidosis (cf. from [4]). Exercise Intervention Acute Effects Bicarbonate Buffers The pair H2CO3/HCO3 possesses a pK value of approximately 4, far outside of the biological pH range. Because of its instability, however, most H2CO3 decays to CO2 and H2O within minutes in absence and within milliseconds in presence of carboanhydrase, reducing the acidifying effect; traditionally the sum of H2CO3 and CO2 is considered as acid with a pK1 of 6.1 at 37 C. But even this pK is slightly outside the physiological pH range. The bicarbonate buffer works, however, very effectively in an open system, that is, with contact to a gas phase where the liberated CO2 can escape; this may be exaggerated by hyperventilation. At a constant CO2 pressure (PCO2), the buffer capacity of bicarbonate is very high at pH 7.4 (2.3 mol mol 1) but decreases with acidification because of a flattening of the titration curve; an average value for physiological pH changes during exercise in plasma and interstitial fluid is about 2 mol mol 1 [1]. In a closed system without excretion of CO2 (apnea or static contraction with stopped blood flow), this buffer has little importance. It is important to state that a buffer salt cannot buffer against its own acid, that is, bicarbonate cannot buffer against CO2. However, the given changes of PCO2 (e.g., D = 20 mmHg) are relatively larger at low values of this quantity (e.g., 30 mmHg) than at high ones (e.g., 60 mmHg) and cause, therefore, larger pH changes in the former case. General Changes markedly influencing acid–base equilibrium during exercise are production of CO2 and increase of lactic acid concentration (other acids like pyruvic acid and fatty acids are negligible); the former occurs always, the latter only if in some tissues aerobic and anaerobic-alactic synthesis of ATP is not sufficient and if the production of lactic acid is larger than its consumption in the rest of the body. Oxygen delivery to the muscle is retarded at the beginning of work because of delay in cardio-pulmonary activation; anaerobic-alactic generation of ATP occurs initially by splitting of CrP with liberation of secondary phosphate, which binds H+. Thus, alkalinization within the fiber happens always during the first seconds. With intense exercise, lactic acid concentration in muscle fibers rapidly begins to increase up to maximal values of approximately 30 mmol l 1; large amounts of lactic acid leave the cells, but the extracellular concentration maximum is always lower because of distribution to the rest of the body and consumption in other tissues. PCO2 rises proportionally to intensity in muscle and venous blood while remaining approximately constant in arterial blood during moderate exercise. If, however, acidification by lactic acid becomes remarkable, the rise is attenuated by hyperventilation; in arterial blood, the values are even lowered. After exercise, the return of high lactic acid levels to control values lasts 3 A 4 A Acid–Base Buffering Systems about 1 h with continuing hyperventilation. Little investigated is the effect of the rising temperature in the body, which in general intensifies the dissociation of acids. Buffering in Muscle Fibers Phosphates. The pK of CrP (4.5) is much lower than cell pH, therefore it does not buffer. The production of ATP by the reaction between CrP and ADP consumes one H+, which is again liberated during the splitting of ATP: CrP2 þ ADP3 þ Hþ ! Cr þ ATP4 ATP4 þ H2 O ! ADP3 þ HPO4 2 þ Hþ But now, the buffer HPO42 (pK = 6.84) binds H+. Consequently, pH rises; there is no contribution to exercise acidosis. During exhausting exercise with 30 mmol l 1 cell water of lactic acid pH decreases from 7.0 to 6.4 ( 0.6 units) exploiting 60% of the nb buffer capacity related to 1 pH unit according to Sahlin [5]. He calculates binding of 15 mmol H+ per liter by liberation of inorganic phosphates from CrP (b = 26 mmol l 1). Already present inorganic phosphate (b = 7 mmol l 1) binds the additional 4 mmol H+. Changes in other phosphates (binding of H+ by ATP and ADP, ATP degraded to AMP and lost after deamination to the extracellular fluid, formation of glucose 6-P and a-glycerol-P) in total, decrease H+-binding by only 1 mmol. Immediately after stopping exercise, CrP is resynthesized, consequently cellular pH drops temporarily before recovery. Proteins and related substances. According to Sahlin, histidine in proteins (b = 15 mmol l 1) and carnosine (b = 2 mmol l 1) bind 11 mmol H+ in his experiments. Together with the preexisting inorganic phosphates, the total amount of non-bicarbonate buffers at rest is 25 mmol l 1, being lower than the range of bnb in mammalian muscle tissue (between 40 and 100 mmol l 1 cell water supplied by histidine-related compounds and inorganic phosphates, with the higher values in fast fibers [4]). The difference can be explained by splitting of CrP during processing of the samples. Bicarbonate buffers. Sahlin [5] calculates a buffer capacity of 12 mmol l 1 for [HCO3 ] during exhaustive bicycle exercise (decrease from 10 to 3 mmol l 1), since CO2 may leave the cells. In any case, the importance of the bicarbonate buffers is reduced compared to the extracellular space because of the low concentration. Total buffers. Summarizing all exploited buffers (15 + 4 1 +11 + 7) yields 36 mmol l 1, which is reasonable because the rise in PCO2 and minor amounts of organic acids add H+ to the 30 mmol of lactic acid. Buffering in Interstitial Fluid and Blood The interstitial fluid without appreciable protein and phosphate content can only buffer against fixed acids using the CO2–HCO3 system. Its capacity amounts to approximately 55 mmol l 1 before exercise (24 mmol l 1 HCO3  2.3), but decreases with consumption of bicarbonate when approaching exhaustion. Thus, the average value for physiological pH changes in plasma and interstitial fluid during hard dynamic exercise is about 47 mmol l 1 [1]. However, capillary wall and erythrocyte membrane are permeable for CO2, HCO3 , Cl , La , and H+ (both latter ions enter the red cells somewhat retarded); therefore blood nb buffers (approximately 30 mmol l 1) are available also for the interstitial fluid. The average bnb for the combined volumes of interstitial fluid and blood amounts to ca. 10–15 mmol l 1 at rest. During exercise, it rises temporarily up to approximately 30 mmol l 1 in untrained subjects. This is mainly caused by increasing extracellular buffer concentrations, because of a water shift to the interior of muscle fibers resulting from osmotic effects of metabolites [1]. Training Effects The total amount of buffers in the body is larger in athletes than in nonathletes because of more muscle mass (especially after resistance training) or a higher blood volume (endurance training). There are some indications that also nb buffer concentration rises in muscle fibers after training (more after high intensity than endurance training). Some increase of carnosine and CrP contents seems to play a role. Finally, upregulation of La and H+ transporters might accelerate the defense against acidosis. Paradoxically, extracellular bnb is attenuated in endurance-trained subjects, the cause being the dilution of Hb in a larger plasma and interstitial volume. Clear differences in bicarbonate concentrations between untrained and trained subjects have never been detected. Altitude Reduction of bicarbonate concentration by renal regulation (nonrespiratory compensation of respiratory alkalosis) and also of muscle mass at extreme altitude decreases the amount of buffers in the whole body. Transport mechanisms for relevant ions (Na+, H+, HCO3 , La , Cl ), however, are improved in muscle and red cell membranes. In contrast to the traditional view, extracellular b is not reduced in altitude dwellers because Hb mass is increased and the extracellular volume is decreased [3]. After training related to moderate hypoxia (living high – training low model as well as classical altitude training) bnb of muscle slightly increases. Acidosis References 1. 2. 3. 4. 5. Böning D, Klarholz C, Himmelsbach B, Hütler M, Maassen N (2007) Extracellular bicarbonate and non-bicarbonate buffering against lactic acid during and after exercise. Eur J Appl Physiol 100:457–467 Böning D, Maassen N (2008) Point: counterpoint “Lactic acid is/is not the only physicochemical contributor to the acidosis of exercise”. J Appl Physiol 105:358–359 Böning D, Rojas J, Serrato M, Reyes O, Coy L, Mora M (2008) Extracellular pH defense against lactic acid in untrained and trained altitude residents. Eur J Appl Physiol 103:127–137 Parkhouse WS, McKenzie DC (1984) Possible contributions of skeletal muscle buffers to enhanced anaerobic performance: a brief review. Med Sci Sports Exer 16:328–338 Sahlin K (1978) Intracellular pH and energy metabolism in skeletal muscle of man. With special reference to exercise. Acta Physiol Scand Suppl 445:1–56 Acidosis MICHAEL I. LINDINGER Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada Synonyms Exercise acidosis; Lactacidosis; Lactic acidosis Definition Acidosis specifically refers to an increase in the hydrogen ion concentration ([H+]; decrease in pH) of the systemic circulation. There are two main types of acidosis that are associated with exercise and recovery from exercise, and these typically occur together with the contributions of each dependent on where the acidosis is assessed, e.g., contracting skeletal muscle, venous blood draining contracting muscle, and arterial blood [4]. A respiratory acidosis is defined as in increase in [H+] caused by or associated with an increase in the partial pressure of carbon dioxide (▶ PCO2).With a respiratory acidosis there typically occurs an increase in the bicarbonate concentration ([HCO3 ]) as described by the Henderson–Hasselbalch equation: Kc
PCO2 ¼ ½Hþ Š
½HCO3 Š A metabolic acidosis is defined as an increase in [H+] caused by or associated with an increase in acid anions, whether they be strong (>90% dissociated in body fluids, e.g., lactate ) or weak (e.g., albumin and phosphate). A metabolic acidosis is typically associated with a decrease in [HCO3 ] because the increase in [H+], in the absence of increase in PCO2, shifts the equilibrium of the CO2 system as follows: A Hþ þ HCO3 $ CO2 þ H2 O Increases in acid anion concentrations and PCO2 produce an acidosis because, physically, they cause an increased dissociation of H+ from water (H+ – OH) [1]. Basic Mechanisms With moderate to high intensity exercise, the systemic (within blood) acidosis of exercise results from three nearly simultaneously occurring events occurring within contracting skeletal muscle. These are: (a) the increased production, accumulation, and release of lactate ; (b) the influx of fluid from the blood, thus raising plasma [protein]; and (c) the increased production and release of CO2 (Fig. 1). The lactate and CO2 produced in muscle rapidly enters venous blood draining muscle, and together with the increase in plasma [protein], results in a marked increase in venous plasma [H+]. The ▶ physicochemical approach is the most useful method for assessing acid–base state and for determining the origins of acid–base disturbances [2, 4, 5]. This approach recognizes three independent variables that determine the concentrations of the dependent variables [H+] and [HCO3 ]. These are the strong ion difference (▶ [SID]), the total concentration of ▶ weak acid anions (▶ [Atot]), and the PCO2. Decreases in [SID], increases in [Atot], and increases in PCO2 independently contribute to the acidosis (increased [H+]). Lactate is a ▶ strong acid anion because it is nearly fully dissociated in solution due to its strong acid pKA of 3.86. With moderate to high intensity exercise, the acidosis within contracting muscle arises from a pronounced decrease in intracellular [SID] that is due to: (1) a decrease in intracellular [SID] and (2) an increase in the PCO2 (2). The decrease in intracellular [SID] is nearly equally due to the increase in [lactate ] and the loss of intracellular [K+] (due to repolarization of action potentials). The increase in PCO2 occurs as a result of increased mitochondrial CO2 production (aerobic metabolism) and from the titration of CO2 stored within the cells. Within venous blood draining contracting skeletal muscle, the plasma acidosis is due to a decrease in [SID], an increase in PCO2, and an increase in [Atot] (Fig. 1). We will use a literature study of four repeated, 30-s bouts of very high intensity leg bicycling exercise to exemplify the contributions of these variables to the acidosis in both femoral venous plasma and in arterial plasma [3]. Femoral venous plasma [lactate ] peaked at 21 ▶ mEq/L and contributed to the 18 mEq/L decrease in [SID]. Plasma PCO2 increased by 50 mmHg to peak at 97 mmHg and [Atot] 5 A 6 A Acidosis Ventilation Venous Blood Arterial Blood [H+] PCO2 [H+] PCO2 Lactate− [SID] Lactate− [SID] [Atot] [Atot] Lactate− K+ H+ CO2 H2O Contracting Muscle Acidosis. Fig. 1 Representation of the major acid–base events occurring within the body during exercise that contribute to the acidosis within venous blood draining contracting muscle and in arterial blood increased by 4 mEq/L to 20.4 mEq/L. The increase in [Atot] is due to the next osmotic flux of fluid into contracting muscle cells. Using the physicochemical approach, it was determined that this decrease in [SID] contributed only 15% to the 54 nEq/L increase in [H+]. In comparison, the increase in PCO2 contributed 75% to the increase in [H+], while the balance was due to the increase in [Atot]. Within arterial plasma, the picture of acid–base status is very different from that in muscle and in femoral venous plasma. As venous blood perfuses the lungs, and in association with the hyperventilation of exercise, the CO2 is eliminated. In this study, this resulted in a marked lowering of plasma PCO2 to 29 mmHg (from as high as 97 mmHg in femoral venous plasma) and in [H+] to 70 nEq/L (compared to [H+] of 100 nEq/L in femoral venous plasma). The elimination of all of the “excess” CO2 at the lungs, and the reduction of PCO2 to below pre-exercise values, helped to restore [H+]. This leaves primarily decreased [SID] and secondarily increased [Atot] contributing to the arterial acidosis. With cessation of exercise, the plasma acidosis gradually resolves due mainly to the restoration of fluid balance, which restores [Atot], and metabolism of lactate , which restores [SID]. Within skeletal muscle, restoration of [SID] also involves the re-accumulation of K+ by the action of the sodium-potassium pump. Exercise Intervention Exercise intensity. In the example provided above, the intensity of exercise was very high, with power outputs 3.5–5 times greater than achieved at VO2 max. This type of exercise produces a very large acidosis that, with repeated exercise bouts, can persist for 90 min of post-exercise recovery. When exercise is performed at an intensity below the lactate threshold, then there may be no acidosis associated with exercise. As exercise intensity increases above the lactate threshold, and continues to the point of voluntary exhaustion, there is a proportional increase in the magnitude and duration of the acidosis. Exercise duration. At submaximal exercise intensities above the lactate threshold, the magnitude of the acidosis is primarily dependent on the intensity. With increasing duration, a new steady state will often be achieved, which can result in a decreasing acidosis as exercise continues, with proportionate decreases in the contributions from PCO2 and lactate . Passive versus active recovery. Recovery of the acidosis of exercise can often be enhanced maintaining low levels of activity, compared to inactivity. Maintaining a low level of activity of the exercised muscle groups during the recovery periods helps to maintain a higher rate of muscle blood flow, cardiac output, and ventilation. Together, these serve to reduce the time needed to achieve a new, post-exercise Activity Dependent Potentiation steady state facilitating transmembrane ion, water, and gas movements between muscle, blood, and other tissues. References 1. 2. 3. 4. 5. Edsall JT, Wyman J (1958) Biophysical chemistry. Academic, New York, p 669 Lindinger MI, Heigenhauser GJ (1991) The roles of ion fluxes in skeletal muscle fatigue. Can J Physiol Pharmacol 69:246–253 Lindinger MI, Heigenhauser GJF, McKelvie RS, Jones NL (1992) Blood ion regulation during repeated maximal exercise and recovery in humans. Am J Physiol Regul Integr Comp Physiol 262: R126–R136 Lindinger MI, Kowalchuk JM, Heigenhauser GJF (2005) Applying physicochemical principles to skeletal muscle acid-base status. Am J Physiol Regul Integr Comp Physiol 289:R891–R894, author reply R904 Lindinger M, Waller A (2008) Muscle and blood acid–base physiology during exercise and in response to training. In: Hinchcliff K, Kaneps AJ, Geor RJ (eds) Equine exercise physiology. Saunders Elsevier, Toronto, pp 350–381 A Action Potentials Action potentials are transient depolarizations of the membrane potential of excitable cells, including neurons and muscle fibers. They play a key role in communication between cells. Action Simulation Action simulation defines cognitive motor states like action observation, motor imagery and action verbalization. These states are not observable, covert stages of action that contain a representation of the action goal, the means to reach the action goal, as well as the consequences of the respective action. Cross-References ▶ Mental Training Acquired Immune Deficiency Syndrome (AIDS) ▶ HIV Actigraphy A method of estimating sleep/wake patterns, accomplished by wearing a monitor that continuously records movements, with each epoch of data classified as sleep or wake based upon algorithms that incorporate movement counts for the epoch in question and the epochs immediately surrounding; for sleep/wake assessment, most commonly worn on the wrist; algorithms used by actigraphy to establish sleep/wake status are typically validated against polysomnography. Activation Induced Cell Death (AICD) AICD occurs in T lymphocytes through previous activation and Fas induced apoptosis. AICD can occur in a cellautonomous manner and is influenced by the nature of the initial T-cell activation events. It plays essential roles in both central and peripheral lymphocyte deletion events involved in tolerance and homeostasis, although it is likely that different forms of AICD proceed via different mechanisms. Active Heating Forced hyperthermia induced by elevating heat production beyond the capacity for heat loss. Achieved via the production of external work, such as during exercise. Actin Actin is a protein that is a major component of the thin filaments. It is a part of the contractile apparatus in muscle cells. Muscles contract by sliding the thin (actin) and thick (myosin) filaments along each other. Actin has the binding sites for the myosin crossbridges. Activity Dependent Potentiation Activity dependent potentiation is the generic term that has been used to describe all forms of enhanced contractile response that can be attributed to prior activation: staircase, 7 A 8 A Acute Febrile Illness posttetanic potentiation and postactivation potentiation (PAP). The cellular mechanism that allows more force for a given activation is thought to be phosphorylation of the regulatory light chains of myosin. Phosphorylation of the light chains increases calcium sensitivity, which means there can be more force for a given level of submaximal calcium concentration. Maximal force is not enhanced, but the peak rate of force development is increased. Posttetanic potentiation, the electrical analogue of PAP, is an enhanced contractile response following an electrically induced tetanic contraction. Staircase is an enhanced contractile response during identical sequential submaximal activations, usually with single pulses of stimulation. However, staircase is also evident during sequential brief incompletely fused tetanic contractions. It is important to realize that in most experimental work on PAP, electrical stimulation has been used to evaluate the enhanced contractile response with a given stimulation; otherwise, it would be difficult to know if the enhanced response was due to extra activations, or a true enhancement of force for a given stimulation. The term complex training has also been used to refer to a high intensity effort, leading in the short-term (minutes) to a subsequent better performance. It is believed that the mechanism contributing to this improvement is the same as the mechanism for PAP, but this has not been confirmed. ▶ Postactivation Potentiation Acute Febrile Illness ▶ Acute Phase Reaction Acute Mountain Sickness DAMIAN M. BAILEY Neurovascular Research Laboratory, University of Glamorgan, Pontypridd, Wales, UK experienced by non-acclimatized mountaineers within 6–12 h of arrival to altitudes above 2,500 m. It is considered a primary disorder of the central nervous system since headache, indistinguishable from that encountered during migraine without aura, is the most common feature. AMS is generally benign though may progress to high-altitude cerebral edema (HACE) in more severe cases or during continued ascent when symptoms of AMS are present. HACE typically occurs above 4,000 m and leads, if left untreated, to death due to brain herniation [1, 2]. Complicated by differences in the clinical definition of AMS, individual susceptibility, rate of ascent and prior exposure have been identified as the major independent risk factors that determine prevalence. In susceptible individuals exposed to 4,559 m, the prevalence of AMS was 7% assuming prior exposure and slow ascent, 29% with prior exposure only, 33% with slow ascent only, and 58% following rapid ascent and no prior exposure. In non-susceptible individuals, the corresponding prevalence was estimated at 4%, 11%, 16%, and 31%, respectively. The overall odds-risk-ratio for developing AMS in susceptible versus non-susceptible individuals was estimated to be 2.9 [2]. Pathophysiological Mechanisms While it is well established that patients with HACE exhibit extracellular (vasogenic) edema subsequent to disruption of the blood–brain barrier (BBB) [1, 2], the situation with AMS is more complex, due in large part to the difficulties associated with clinical diagnosis. Traditionally, AMS has been considered a mild form of HACE and that both syndromes share a common pathophysiology linked by vasogenic edematous brain swelling and intracranial hypertension at opposing ends of a clinical continuum. However, recent studies employing diffusion-weighted (DW)-magnetic resonance imaging (MRI) have questioned this paradigm and since provided insight into alternative mechanisms [1]. The subsequent discussion will critically appraise each of the traditional and newly emerging components currently implicated in the pathophysiology of AMS. These are summarized schematically in Fig. 1 and will take the form of Phases I–III. Synonyms Phase I: The Stimulus Altitude illness; Altitude sickness; Hypobaropathy Hypoxia: Although ▶ hypoxia is not the immediate cause of AMS since symptoms typically take 6 h to evolve, it is the primary stimulus since symptoms typically become worse with increasing altitude and relieved by normalizing the inspiratory PO2. Furthermore, it has been suggested that AMS-susceptible subjects are systemically more Definition Acute mountain sickness (AMS) describes a collection of nonspecific vegetative symptoms that include headache, anorexia, nausea, vomiting, fatigue, dizziness, and insomnia Acute Mountain Sickness A A INSPIRATORY HYPOXIA I ↑Sympathetic activation ↑Activation of reninangiotensin system ↑Sensitivity-reactivity to hypoxemia ↓Gas exchange ↑Genetic pre-disposition Impaired cerebral bio-energetics Molecular Stress (Capillary leak) ↑Oxidative-nitrosative-inflammatory stress II Mechanical Stress (Hyper-perfusion) ↓Autoregulation ↑Capillary pressure ↑Capillary permeability Blood-brain barrier disruption Primary vasogenic (extracellular) edema Fluid “re-distribution” (Extra → Intracellular space) Secondary cytotoxic (intracellular) edema ↑Trigeminal activity-reactivity ↑Pain perception III Cerebral capillary “stress-failure” with microhemorrhages AMS (Minor BBB disruption) HACE (BBB failure) Acute Mountain Sickness. Fig. 1 Schematic of the major pathways involved in acute mountain sickness and high-altitude cerebral edema hypoxemic or equally, more reactive to hypoxemia for any given inspirate during wakefulness and sleep compared to their healthier counterparts. Tentative evidence suggests that a blunted hypoxic ventilatory response and sympathetic activation leading to activation of the reninangiotensin system, fluid retention, and subclinical interstitial pulmonary edema may prove additional risk factors that further compound hypoxia subsequent to impaired gas exchange and thus account for the increased sensitivity-reactivity. However, evidence of interstitial pulmonary edema in AMS is at best indirect and inconsistent, while fluid retention might prove the consequence rather than the direct cause of AMS [2]. Since a previous history has been identified as one of the most reliable predictors of illness during subsequent ascent, there may be some innate predisposition to AMS. Subsequent investigations have focused on candidate gene 9 polymorphisms in an attempt to identify potential genetic variants underlying susceptibility. Recent interest has focused on the angiotensin-converting enzyme (ACE) gene since the insertion (I) allele has previously been associated with elite mountaineering status and successful ascent to 8,000 m peaks. However, studies have failed to support any association between ACE genotype and susceptibility to AMS. While the current evidence has failed to identify a genetic contribution to AMS, it is important to emphasize that the sample sizes of all the aforementioned studies are too small for genetic association studies. Furthermore, “genetophysiology” is very much in its infancy with only 20 out of 25,000 genes in the human genome and only 50 out of millions of polymorphisms currently assessed for roles in hypoxic (mal)-adaptation and altitude illness. 10 A Acute Mountain Sickness Phase II: The Response Impaired cerebral bioenergetics: While existing measurement techniques have failed to identify any evidence for a “global” cerebral O2 deficit in the severely hypoxichypocapnic human [3], positron-emission tomography studies have revealed striking spatiotemporal differences in the brain’s “regional” energy consumption. Furthermore, neurotransmitters, the ubiquitous regulators of neuronal activity, are particularly vulnerable to hypoxia in light of their correspondingly high Michaelis constant for O2. Thus, it is conceivable that even mild arterial hypoxemia could result in focal cerebral deoxygenation and impaired bioenergetic/neuronal communication with further decrements expected due to the “additional” deoxygenation associated with AMS. Molecular-mechanical stress: Focal impairments in cerebral oxygenation have the potential to promote capillary leakage (molecular stress) and hyper-perfusion (hemodynamic stress), established risk factors that conspire to disrupt the BBB. Much interest has focused on the hemodynamic pathway since increased cerebral blood flow (CBF) occurs in response to hypoxia and impaired autoregulation has recently been documented in AMS [4]. These findings suggest that the AMS-brain is less capable of “buffering” rapid surges in arterial pressure and thus potentially more vulnerable to hyperperfusion. A pressure-passive rise in regional CBF could translate into increased capillary hydrostatic pressure, though this is yet to be confirmed in humans. Elevated intravascular pressure could cause vasogenic edema subsequent to hydrostatic disruption of the BBB. Oxidative-nitrosative-inflammatory stress constitutes an alternative, albeit complementary, pathway that can further compound barrier disruption through its (molecular) impact on capillary permeability. A recent study provided direct electron paramagnetic resonance (EPR) spectroscopic evidence for an increased release of lipid-derived alkoxyl-alkyl (LO●-LC●) radicals and associated reactive oxygen-nitrogen species (ROS-RNS) across the hypoxic human brain in direct proportion to AMS symptom scores [3]. Furthermore, dietary antioxidant vitamin supplementation provided some, albeit mild, prophylactic benefit, though further research employing larger sample sizes with improved methods of delivering novel antioxidant vehicles across the BBB to the brain parenchyma is warranted [1]. These findings indicate that the AMS-brain is especially vulnerable to molecular attack by free radicals which is not surprising given its modest antioxidant defenses, abundance of transition metals, auto-oxidizable neurotransmitters, and neuronal membrane lipids rich in polyunsaturated fatty acid side-chains exposed to a disproportionately high O2 flux [1]. The LO●-LC● species detected in hypoxia are associated with the impaired autoregulation observed in AMS [4], and they are thermodynamically capable of causing direct structural damage to the BBB microvascular endothelium, neurons, and glia and promoting cell swelling through down-regulation of Na+/K+-ATPase, Ca2+-ATPase, calmodulin-associated Ca2+-ATPase, and Na+–Ca2+ exchanger activities [1]. Since free radicals are so reactive with lifetimes (t1/2) in the order of 10 3–10 9 s, they may prove the “upstream” initiators of comparatively longer-lived inflammatory biomolecules. Indeed, current evidence suggests that hypoxia is associated with mild inflammation as indicated by a systemic increase in Pro-inflammatory cytokines. Inflammatory “priming” prior to exposure to hypoxia with exercise, heat, and intravenous endotoxin infusion has been shown to increase susceptibility to AMS (Bailey et al., unpublished findings). These observations may also help explain the link between obesity and AMS since the former is characterized by chronic vascular oxidation-inflammation. Animal models have demonstrated that hypoxia stimulates vascular endothelial growth factor (VEGF) resulting in vascular leakage and cerebral edema tempting speculation that it’s expression may predispose to high-altitude illness. Human studies have since failed to demonstrate any relationship between blood and/or cerebrospinal fluid concentrations of “total” VEGF and AMS [5]. However, this may be due to the fact that differences in the “free” concentration of VEGF mediated largely by its soluble receptor (sFlt-1) which serves to bind VEGF thus reducing vascular leak and angiogenesis were not evaluated. Hence, a recent study demonstrated a greater increase in “free” VEGF and “blunted” rise in sFlt-1 at high altitude in subjects with AMS compared to controls suggesting that it may well prove a molecular risk factor. BBB integrity and vasogenic edema: Figure 1 describes how this combination of molecular-mechanical stress “arrives” at the brain, ultimately compromizing barrier integrity and encouraging the formation of extracellular (vasogenic) edema. This was recently confirmed by DWMRI which established the “signature” rise in brain volume, T2-relaxation time, and apparent diffusion coefficient during hypoxia characteristic of mild vasogenic edematous brain swelling [6]. These changes were particularly pronounced in the splenium and genu of the corpus callosum, the same predilection site to that observed in HACE, likely the result of its unique vascular anatomy; densely packed horizontal fibers characterized by short Acute Mountain Sickness arterioles that lack adrenergic tone may render it more susceptible to hyper-perfusion edema in the setting of hypoxic cerebral vasodilatation. In contrast, previous studies have failed to detect any changes in the cerebrospinal fluid (CSF)-blood protein concentration quotients [5] and trans-cerebral release of the astrocytic protein S100b, a surrogate biomarker of BBB integrity [3]. In combination, these studies imply that the extent of barrier disruption in hypoxia is so subtle that it is beyond standard biomolecular detection limits. Follow-up studies employing gadolinium-enhanced MRI will provide a more accurate assessment of the extent of barrier disruption in hypoxia. Traditional opinion suggests that AMS is the direct consequence of elevated intracranial pressure (ICP) caused by more pronounced vasogenic edematous brain swelling in hypoxia [7]. Intracranial hypertension has been implicated as the primary stimulus responsible for cephalalgia through mechanical activation of the trigeminovascular system (TVS). However, DW-MRI has consistently failed to support this concept with no relationships observed between the hypoxia-induced increases in brain volume or T2rt and cerebral AMS scores. Mild vasogenic edematous brain swelling therefore appears to be an incidental finding that occurs in all brains exposed to the hypoxia of high-altitude [5, 6]. Furthermore, the observation that intracranial volume (ICV) is not increased to any greater extent in the AMS-brain argues against intracranial hypertension as a significant event. The recent increases observed in optical disc swelling and optical nerve sheet density as measured by ultrasound were often minor and not consistently related to AMS scores. Thus, there is no convincing human evidence to date to suggest that ICP is raised in AMS [1, 2]. Intracranial-intraspinal buffering capacity: Borne out of an original hypothesis developed over 20 years ago, the lack of correlation between brain swelling and AMS symptoms has since been ascribed to anatomical differences that determine how effectively the human skull can accommodate swelling through displacement of cranial CSF to extracranial compartments [7]. Thus, individuals characterized by a smaller ratio of cranial CSF to brain volume (popularized as the “tight-fit” brain) would be expected to be more prone to intracranial hypertension and thus by consequence AMS, since they are less capable of “buffering” the volume increase through changes in CSF dynamics due to an inadequate cranio-spinal axis CSF reserve. To date, only one human study has provided indirect evidence to support the “tight-fit” hypothesis with AMSsusceptible subjects identified as having comparatively A larger brain to intracranial volume ratios that was apparent even at sea level [6]. However, we are not entirely convinced that this has any bearing on the pathophysiology of AMS. It would seem highly unlikely that the minor volumetric changes of 0.6–0.8% of total brain volume would translate into any physiologically meaningful changes in the mechanical displacement of pain-sensitive structures capable of activating the trigeminovascular system (TVS) [1]. The small increases in ICV documented in the literature likely occupy the flat part of the ICP-volume curve and eminently well buffered by semielastic membranes and changes in CSF dynamics. Cytotoxic edema: To date, the “only” defining morphological feature that distinguishes the AMS-prone from the healthy brain as revealed by DW-MRI is a selective decrease in apparent diffusion coefficient (ADC) scores [6] taken to reflect (secondary) intracellular (cytotoxic) edema “superimposed” upon preexisting (primary) extracellular vasogenic edema. Since both studies failed to provide any evidence for additional edema or swelling, the attenuation of the ADC likely reflects “fluid redistribution” from within the extracellular space (ECS) as intracellular (astrocytic) swelling proceeds without any additional increment in brain volume, edema, or ICP [1]. The cause of this is unknown, but may reflect “pump failure” subsequent to a down-regulation of Na+/K+-ATPase activity triggered by the prevailing oxidative-nitrosative-inflammatory milieu [1]. However, the critical question is whether the symptoms of AMS are caused by such a “minor” translocation of water from the ECS into the cells of the corpus callosum that entered as a result of mild vasogenic edema in hypoxia. This is highly unlikely since edema of the corpus callosum would typically give rise to a disconnection syndrome (e.g., associative agnosia). Headache, its leading symptom, is more likely associated with functional alterations in alternative structures, notably the brainstem. Phase III: The Phenotype Thus, the current findings suggest that AMS and HACE share similar features in that there is an underlying vasogenic component ranging from mild to severe. However, Phase III of Fig. 1 represents the point of “departure” from traditional theory since the edema cannot be held responsible for the symptoms of AMS. Furthermore, the clinical observation that HACE can develop rapidly in the “absence” of preceding AMS, and that in a large cohort of 66 cases with HACE, 33% had no headache, further questions the concept that the AMS-to-HACE symptom complex can be explained by this continuum of mild to severe cerebral edema [2]. 11 A 12 A Acute Mountain Sickness Pain and the trigeminovascular system (TVS): Preliminary evidence suggests that AMS may be the result of altered pain perception and trigeminovascular nociceptive input from the meningeal vessels during hypoxia. Direct inhibition of TVS activity with oral sumatriptan, a selective 5-hydroxytryptamine (HT)1 receptor subtype agonist, was shown to reduce the relative risk of AMS by as much as 50% in the largest randomized trial to date. In addition to its ability to attenuate cell excitability in trigeminal nuclei via stimulation of 5-HT1B/1D receptors within the brainstem and vasoconstriction of meningeal, dural, cerebral, or pial vessels, sumatriptan can also scavenge nitric oxide, superoxide, and hydroxyl radicals. Thus, direct activation of the TVS through oxidative-nitrosativeinflammatory stress may prove the final common pathway since, consistent with the current evidence, it does not rely on any volumetric changes to the brain. The recent observation that AMS did not influence the (steady-state) cerebral metabolism of the “migraine-molecule” calcitonin gene related peptide (CGRP) [8] argues against “sustained activation” of the TVS as an important event. However, this finding does not exclude acute release from trigeminal perivascular nerve fibers, the site of nociception during the early phase of hypoxia and the lack of major breach in the BBB may have also prevented intrathecally formed CGRP from entering the extracranial circulation in sufficient amounts to permit molecular detection. This finding also argues a need to focus on the cerebral metabolism of alternative redox-reactive biomarkers that are equally capable of activating the TVS in the acute term [3]. The link to HACE: While HACE has traditionally been ascribed to vasogenic edema [7], it is reasonable to assume that a cytotoxic component may also be present since hypoxemia is likely more severe compared to AMS. Therefore, cell swelling should be even more pronounced in HACE. However, ADC mapping has not been performed immediately following evacuation from altitude in patients with HACE. A recent study combined conventional T2∗ with a novel, highly sensitive susceptibility-weighted MRI technique to reveal multiple “microbleeds” detected as hemosiderin deposits confined to the genu and splenium of the corpus callosum of patients with a history of HACE that had occurred up to 3 years ago [1]. Erythrocyte extravasation was taken to reflect cerebral capillary “stress failure” subsequent to cerebral hyper-perfusion and severe BBB disruption. The failure to detect any hemosiderin deposits in subjects diagnosed with severe AMS reinforces the fundamental concept that vasogenic edema is minor in AMS and is unlikely to account for symptoms and points to a novel diagnostic feature that further discriminates AMS from HACE. Diagnostics/Treatment Headache is the cardinal symptom of AMS and is associated with, if not the primary trigger for, anorexia, nausea, vomiting, fatigue, dizziness, and insomnia. There are no diagnostic physical findings in benign AMS, although the onset of ataxia and altered consciousness signal clinical progression to HACE. The Lake Louise (LL) and Environmental Symptoms Questionnaire Cerebral (ESQ-C) scoring systems are the subjective tools most commonly employed to rate AMS. A LL score of 5 points and ESQ-C score of 0.7 points in the presence of headache and following a recent gain in altitude signals the presence of clinically significant (i.e., moderate-to-severe) AMS [2]. AMS can be prevented by gradual ascent thus ensuring adequate time for acclimatization. Analgesics for the symptomatic relief of headache and day of rest are recommended for mild to moderate AMS. If no improvement is observed, the individual should descend. Severe AMS can be managed through immediate descent or the administration of low-flow oxygen (1–2 L/min). If descent and oxygen are unavailable, dexamethasone (4 mg every 6 h) is advised. Acetazolamide (250 mg twice daily) might be considered for mild to moderate AMS in a setting where further ascents must be made as a mixed therapeutic and prophylactic intervention. Prophylaxis is recommended in individuals with a history of AMS when slow ascent is not possible or for those with unknown susceptibility who plan to ascend above 3,000–4,000 m (sleeping altitude) within 1–2 days [2]. References 1. 2. 3. 4. 5. Bailey DM, Bartsch P, Knauth M, Baumgartner RW (2009) Emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological. Cell Mol Life Sci 66(22):3583–3594 Bartsch P, Bailey DM, Berger MM, Knauth M, Baumgartner RW (2004) Acute mountain sickness: controversies, advances and future directions. High Alt Med Biol 5:110–124 Bailey DM, Taudorf S, Berg RMG, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K (2009) Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol 297(5):R1283–R1292 Bailey DM, Evans KA, James PE, McEneny J, Young IS, Fall L, Gutowski M, Kewley E, McCord JM, Moller K, Ainslie PN (2009) Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function. J Physiol 587(1):73–85 Bailey DM, Roukens R, Knauth M, Kallenberg K, Christ S, Mohr A, Genius J, Storch-Hagenlocher B, Meisel F, McEneny J, Young IS, Steiner T, Hess K, Bartsch P (2006) Free radical-mediated damage Acute Phase Reaction 6. 7. 8. to barrier function is not associated with altered brain morphology in high-altitude headache. J Cereb Blood Flow Metab 26(1):99–111 Kallenberg K, Bailey DM, Christ S, Mohr A, Roukens R, Menold E, Steiner T, Bartsch P, Knauth M (2007) Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab 27(5):1064–1071 Hackett PH, Roach RC (2001) High-altitude illness. N Engl J Med 345:107–114 Bailey DM, Taudorf S, Berg RMG, Jensen LT, Lundby C, Evans KA, James PE, Pedersen BK, Moller K (2009) Transcerebral exchange kinetics of nitrite and calcitonin gene-related peptide in acute mountain sickness: evidence against trigeminovascular activation? Stroke 40(6):2205–2208 Acute Phase Proteins (APPs) During the acute phase reaction, the liver expresses rapidly new proteins named APPs. APPs recognize infectious agents, tissue breakdown products, and numerous other homotopes. Some APPs activate innate immune cells, mediate neutralization, and cytotoxicity; others are enzyme inhibitors or anti-inflammatory agents. Thus, the liver is a key organ in acute illness by providing APPs on a very short notice. A Characteristics Hans Selye discovered that rats develop a specific syndrome when exposed to various “nocuous” agents: The adrenal glands were enlarged, the thymus and other lymphoid tissues developed atrophy, and there were bleedings in the gastrointestinal tract [2]. Selye called the noxious agents stressors, which elicited the stress response. Later Selye realized that stressed animals can resist damaging agents with elevated resistance. He argued that this resistance was a defense reaction and named it the general adaptation syndrome [3]. Selye also defined the stress reaction, which is the first and a fairly accurate description of the acute phase reaction as we know it today [2]. Historically fever has been regarded as a healing reaction. So Boivin purified bacterial LPS for the purposes of fever therapy. LPS is a very effective pyrogen. Today we know that detoxified LPS is in fact a very effective stimulant of the innate immune system and indeed, it is capable of increasing host immunity in animals and in man in critical illness [2]. The Immune System We distinguish specific or adaptive immunity and innate or natural immunity [4]. Adaptive Immunity Acute Phase Reaction ISTVAN BERCZI Department of Immunology, The University of Manitoba, Winnipeg, MB, Canada Synonyms Acute febrile illness; Acute phase response; General adaptation syndrome Definition Acute phase reaction (APR) is a systemic host defense response against infectious agents, and to a great variety of noxious insults that are harmful to the host. During APR innate immune mechanisms are activated, which induce APR, a highly coordinated and very effective defense reaction against the initiating insults. Neuroendocrine and metabolic changes, catabolism, and fever are the hallmarks of APR. APR may be regarded as a host defense response whereby the adaptive immune system (ADIM) failed to control a problem (e.g., infection) so it became necessary for the innate immune system (INIM) to mount an emergency host defense response, which is APR [1,2]. The adaptive immune system is also known as thymus dependent, or T lymphocyte dependent immunity. T lymphocytes mature in the thymus gland. We distinguish helper (Th1, Th2) killer or cytotoxic (Tk, CTL) and suppressor/regulatory (Tsr Treg) lymphocytes [4]. Helper T lymphocytes (Th1) generate CTL and delayed type hypersensitivity reactions, which are classified as cell-mediated immunity. Th2 helper cells stimulate bone marrow–derived (B) lymphocytes to secrete antibodies, which mediate humoral immunity. Suppressor regulatory cells are a heterogeneous group of cells, which include several types of Tsr, suppressor monocyte/macrophages. Suppressor antibodies and cytokines, such as interleukin (IL)-10, and transforming growth factor-beta [(TGF)-beta] also regulate immune function. T and B lymphocytes develop antigen-specific surface receptors, which undergo somatic mutation and clonal selection after stimulation by the specific antigenic determinant (epitope). The B and T cells bearing such receptors show exquisite specificity to the epitope that stimulated their maturation. The T cells develop into mature effector cells (e.g., helper, killer, regulatory), whereas B lymphocytes secrete antigen-specific antibodies [4]. Specific immune responses are initiated by antigen presenting cells (APCs), which could be a macrophage or 13 A 14 A Acute Phase Reaction dendritic cells (DCs), which are “professional” APCs. APCs are phagocytic cells, they ingest the antigen and digest (process) it and peptides of the antigen (epitopes) are expressed in the grooves of the surface MHC-I (MHC-I-Ag) molecules of APC, which are recognized by Th1 cells. B lymphocytes also present antigen to helper Th2, via MHC II-Ag on their surface. Helper T lymphocytes then stimulate the proliferation and maturation of immature T and B cells into mature effector cells that mediate cell-mediated and humoral immunity. Such T cells recognize the MHC-Ag complexes and secrete interleukins (e.g., IL2, -4, -6, etc.), which are growth and differentiation signals for the immature lymphoid cells [4]. Adaptive immune reactions may be induced by injection of the antigen by various routes to animals and humans. Immunity will develop within a week or more because cell proliferation is necessary for clonal expansion, which takes time, and then the cells must differentiate into mature effector cells that mediate the specific immune responses [4]. Innate or Natural Immunity Traditionally it was held that INIM was initiated by monocytes and macrophages that recognize foreign material in general and induced nonspecific immunity, or natural immunity via stimulating leukocytes to eliminate the invader organism or insult. This latter term indicates that this immunity could not be induced but was always there naturally. Indeed, we are born with this form of immunity; it is always with us until our last moment of life, protecting us for a lifetime. INIM has the capacity to protect us instantaneously, no immunization is necessary [3]. LPS turned out to be an excellent stimulator of natural antibodies, which could not be stimulated by traditional immunization. LPS was also a potential stimulant of host resistance in general. When natural antibodies were examined, it was clear that they recognize highly cross-reactive antigens specifically. LPS is also present in all gramnegative bacterium species, regardless of pathogenicity. We proposed that evolutionarily highly conserved cross-reactive (homologous) epitopes (homotopes) are recognized by INIM. LPS is one such homotope. Others emphasized the pattern nature of recognition. Natural killer cells recognize “missing self ” and kill cells without surface MHC proteins. So the term “nonspecific immunity” had to be replaced with poly-specific immunity. Toll-like receptors and a number of other cell surface molecules function as INIM receptors (INIRs) for antigen [3]. Recently it has been discovered that toll-like receptors, which are the best studied INIR, are expressed by neurons, glia cells, in all leukocytes, in the pituitary gland, in the adrenal gland, in the liver, in mucosal epithelial cells, in endothelial cells, in vascular smooth muscle, and also in the cornea. These facts suggest that the entire body, including the CNS, endocrine organs, the liver, epithelium, and endothelium, and possibly even more, participate in innate immune host defense. The CNS is capable of directly sensing infectious agents through TLR, and react instantaneously by causing inflammation, the final effector response of all immune compartments. Similarly the pituitary produces proopiomelanocortin (POMC) in response to LPS (TLR4 is involved), mucosal epithelial TLR participates in inflammation and responds to pathogens, corneal TLR was found to fight infection, and endothelial TLR was observed to play important roles in homeostasis of the heart. Therefore, in addition to participating in NATIM, TLR fulfills important physiological functions [5]. Cytokines show similar poly-specific action, especially IL-1, -6 and tumor necrosis factor (TNF)-alpha, which have a prominent role in the induction of APR [2]. Neuroendocrinology of APR The Central Nervous System (CNS) The CNS is able to sense directly infectious and noxious agents via innate immune receptors, such as TLR. Nerves have also such receptors as well as receptors for cytokines, so sensory nerves will carry the signals of infection/insult to the paraventricular nucleus in the hypothalamus. Moreover, the cytokines that induce APR (IL-1, -6; TNFalpha) are able to signal the brain directly. Several mechanisms have been proposed for this direct signaling pathway. The hypothalamic centers regulating the HPA axis, and the sympathetic nervous system are activated. Fever develops [2]. The Hypothalamus-Pituitary-Adrenal (HPA) Axis Corticotrophin-releasing hormone (CRH) and vasopressin (VP) are the hypothalamic regulators of adrenocorticotropic hormone (ACTH), which is secreted by the pituitary gland and it stimulates glucocorticoid (GC) production in the adrenal cortex. This axis is activated invariably during APR. GC catecholamine (CAT) productions are increased (sympathetic outflow) during APR. The HPA axis has an immunoregulatory and anti-inflammatory role during APR. GC and CAT amplify INIM mechanisms, and stimulate Tsr cells, which in turn suppress ADIM. ADIM Acute Phase Reaction reactions need a long time to develop, so this system is not capable of instantaneous host defense. ADIM is suppressed in a reversible fashion. The INIM system takes over host defense entirely during APR [1]. Growth hormone and prolactin (GLH) rise quickly for a few hours during APR, which temporarily amplify ADIM mechanisms. If this does not resolve the problem, GLH become suppressed, and the HPA axis will coordinate the next phase of host defense. Insulin, glucagon, and leptin are elevated during APR. There is insulin resistance. Epinephrine, norepinephrine, and aldosterone are also elevated. Thyroid and sex steroid hormones are suppressed [2]. Immune Activation in APR The bone marrow is activated and produces elevated amounts of monocytes and granulocytes. B cells producing natural antibodies are also activated. The thymus is involuted [2]. Monocyte/macrophages are the key cells that recognize the infection/insult by their INIR and secrete the cytokines IL-1, IL-6, and TNF-alpha which act on the CNS, activate leukocytes, stimulate bone marrow function, induce acute phase production in the liver, increase complement and the coagulation system [2]. A and mannose binding lectin. Enzymes and enzyme inhibitors, antioxidants, anti-apoptotic and anti-inflammatory proteins, and other bioactive molecules, such as complement components, coagulation factors, fibrinogen, etc. During APR, C-reactive protein and serum amyloid A may increase over 1,000-fold in the serum within 24 h [2]. Systemic Inflammatory Response APR may be regarded as a systemic inflammatory response. Bone marrow–derived white blood cells are the effectors, equipped with natural antibodies, supported by the complement system and by a myriad of cytokines. Phagocytosis and cytotoxicity are the main mechanisms of clearance of noxious agents. Blood coagulation also plays a role, perhaps to localize pathogens. During APR, the CNS, the bone marrow, WBC, and the liver are activated. The other tissues undergo catabolism, which is essential for fueling the immune system. Treatment with anabolic hormones, such as growth hormone, interferes with the catabolic process, and consequently with host defense [2]. Healing, Recovery Pathophysiology of APR The hypothalamic regulators of APR are CRH and VP. However when APR is subsiding CRH becomes inactive and VP will regulate healing and recovery. VP regulates the HPA axis, and also PRL, it is capable to create the homeostatic conditions, which lead to recovery and restoration of normal immune function [1]. Cytokines Clinical Relevance In addition to the cytokines that initiate APR, leukemia inhibitory factor (LIF), IL-8, -10, interferon (IFN)gamma, TNF synthesis inhibitor, interleukin receptor antagonist, platelet activating factor, colony stimulating factors, prostaglandins, and thromboxanes were shown to play a role in APR [2]. Clinically APR is characterized by fever, inactivity, somnolence, loss of appetite, and weight loss. If there is no recovery, multiple organ failure and death will follow. However most individuals encounter febrile illness on numerous occasions during their lifetime and survive. This experience makes it very clear that APR is very efficient in protecting the host. Much information is available about the biology and medical significance of CRP. Serum levels of CRP are used clinically for diagnosing inflammatory disease. In Crohn’s disease (CD) serum levels of CRP correlate well with disease activity and with other markers of inflammation. CRP is a valuable marker for predicting the outcome of certain diseases as coronary heart disease and hematological malignancies. An increased CRP (>45 mg/L) in patients with inflammatory bowel disease predicts with a high certainty the need for colectomy, and this by reflecting severe ongoing and uncontrollable inflammation in the gut. CRP is also a diagnostic marker in systemic lupus erythematosus [2]. Natural Antibodies A special subset of B lymphocytes (CD5+) belong to INIM. They respond directly to infection and insults by natural antibody production. Such antibodies typically recognize highly cross-reactive homotopes on microbes and provide protection in a poly-specific manner [3]. Acute Phase Proteins Liver proteins change significantly during APR. Very rapidly under the influence of IL-6 and glucocorticoids, the liver will synthesize the so-called acute phase proteins (APPs). APPs consist of molecules serving host defense, such as C-reactive protein, endotoxin binding protein, 15 A 16 A Acute Phase Response Strenuous exercise increased plasma levels of TNFalpha, IL-1, IL-6, IL-1 receptor antagonist, TNF receptors, IL-10, IL-8, and macrophage inflammatory protein-1. IL-6 increased up to hundredfold after a marathon race and the increase was tightly related to the duration and intensity of the exercise. IL-6 is produced in the skeletal muscle in response to exercise. Exercise induces immune changes and also alters neuroendocrinological factors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids. Exercise-associated muscle damage initiates the inflammatory cytokine cascade. LPS enters the circulation in athletes after ultra-endurance exercise and may, together with muscle damage, be responsible for the increased cytokine response and hence GI complaints [2]. Cachexia is the clinical consequence of a chronic, systemic inflammatory response. There is redistribution of the body’s protein content, with preferential depletion of skeletal muscle and an increase in the synthesis of APP involved in APR [2]. The anorexia of infection is part of the host’s APR and is beneficial in the beginning, but deleterious, if long lasting. Bacterial cell wall compounds (e.g., LPS, peptidoglycans), microbial nucleic acids and viral glycoproteins trigger the APR and anorexia by stimulating the production of proinflammatory cytokines (e.g., interleukins, TNF, interferons), which serve as endogenous mediators. The central mediators of the anorexia during infection appear to be neurochemicals involved in the normal control of feeding, such as serotonin, dopamine, histamine, CRF, neuropeptide Y, and MSH. Reciprocal, synergistic, and antagonistic interactions between various pleiotropic cytokines, and between cytokines and neurochemicals, form a complex network that mediates the anorexia during infection [2]. Aging is associated with increased inflammatory activity, increased circulating levels of TNF, IL-6, cytokine antagonists, and acute phase proteins. Chronic low-grade inflammation in aging promotes an atherogenic profile and is related to age-associated disorders (e.g., Alzheimer’s disease, atherosclerosis, type 2 diabetes, etc.) and enhanced mortality risk. A dysregulated production of inflammatory cytokines, delayed termination of inflammatory activity, and a prolonged fever response suggest that the acute phase response is altered in aging [2]. The metabolic syndrome is characterized by cardiovascular and diabetes risk factors generally linked to insulin resistance, and obesity. Cross-sectional analysis demonstrated that markers of inflammation and endothelial dysfunction predict the development of diabetes mellitus and weight gain in adults. There is biological evidence to suggest that chronic activation of the innate immune system may underlie the metabolic syndrome [2]. In allergic patients, increased IL-6 levels correlated with greater erythema extent, lower mean arterial blood pressure, and a longer duration of symptoms. There was an inverse relationship between CRP and histamine levels [2]. In patients with rheumatoid arthritis (RA), IL-6 correlated closely with CRP and with erythrocyte sedimentation rate (ESR). These three parameters correlated well with serum cortisol, which is increased in active RA [2]. CRP and C3a levels were significantly higher in patients with IgA nephropathy as compared with healthy controls and with patients with hypertension or nonimmune renal diseases. Mean CRP but not C3a levels were significantly higher in IgA nephropathy patients with disease progression than in those with stable renal function [2]. References 1. 2. 3. 4. 5. Berczi I, Quintanar-Stephano A, Kovacs K (2009) Neuroimmune regulation in immunocompetence, acute illness, and healing. Ann N Y Acad Sci 1153:220–239 Berczi I, Szentivanyi A (2003) The acute phase response. In: Berczi I, Szentivanyi A (eds) Neuroimmmune biology, vol 3, The immuneneuroendocrine circuitry. History and progress. Elsevier, Amsterdam, pp 463–494 Bertok L, Chow DA (2005) Natural immunity. In: Berczi I. Szentivanyi A, Series (eds) Neuroimmune biology, vol 5. Elsevier, Amsterdam Janeway CA, Travers P, Walport M, Schlomchik MJ (2005) Immunobiology. Galand science. Taylor and Francis Group, New York/London Berczi I (2010) Antigenic recognition by the brain. The brain as an immunological organ. In: Berczi I (ed) New insights to neuroimmune biology. Elsevier, Amsterdam, pp 145–154 Elsevier Insights, www.amazon.com Acute Phase Response ▶ Acute Phase Reaction Acute Polio Infection of the Central Nervous system by the polio virus, leading to acute flaccid paralysis of muscles by destruction of the motor neurons in the spinal cord. Adenosine Acute Program Variables The features of a resistance training protocol that impact its physiological stimuli to the body, i.e., choice of exercises, order of exercises, amount of rest between sets and exercises, number of sets, and the intensity of the resistance used. Adaptability ▶ Neural Plasticity Adaptation Refers to any beneficial, or presumably beneficial, change to the structure or function of an organ or the whole body in response to chronic exercise training. Cross-References ▶ Cold ▶ Training, Adaptations Adaptive Immune Cells ▶ Lymphocytes Adaptive Immune System (ADIM) The adaptive immune system is also known as thymus dependent, or T lymphocyte dependent immunity. T lymphocytes mature in the thymus gland. We distinguish helper (Th1, Th2) killer or cytotoxic (Tk, CTL) and suppressor/regulatory (Tsr, Treg) lymphocytes. T cells mediate antigen-specific cellular immunity and regulate immune function. Bone marrow–derived (B) lymphocytes produce antigen-specific antibodies. Cross-References ▶ Lymphocytes A Adaptive Movement Variability Also known as functional or compensatory variability, this type of neurobiological system variability emerges in coordination of a performer during attempts to satisfy changing task constraints during sport performance. The traditional idea of variability representing “noise” in a neurobiological system is eschewed in ecological dynamics in favor of a more functional role for movement pattern variability in adapting to changes in the performance environment, due to factors like changes in ambient temperature, performance conditions, and fatigue. Whilst this idea is understandable in coordination of multi-articular actions in dynamic environments such as team games, adaptive movement variability have also been observed to play a functional role in helping athletes adjust coordination patterns in more stable task environments such as pistol shooting, archery, and diving. Adaptive Physical Activity (APA) Physical activity for fitness and aerobic conditioning that has been modified to meet the needs of individuals with physical limitations. Adenine Nucleotides The adenine nucleotides are forms of adenosine that are phosphorylated, or contain one or more phosphate groups. The adenine nucleotides include adenosine 50 -triphosphate (ATP), adenosine 50 -diphosphate (ADP), and adenosine 50 -monophosphate (AMP). Cross-References ▶ Adenosine Triphosphate Adenosine Adenosine is an endogenous purine nucleoside comprised of adenine and a ribose sugar that modulates many physiological processes via G protein coupled adenosine receptors. It contributes to energy exchange as a component of 17 A 18 A Adenosine 50 -Monophosphate-Activated Protein Kinase adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). It also plays a role in cellular signaling as a component of cyclic adenosine monophosphate (cAMP). Adenosine is a vasodilator and a central nervous system inhibitor. Pharmacologically, it is also used as a cardiac antiarrythythmic. Adenosine 50 -MonophosphateActivated Protein Kinase ▶ AMP-Activated Protein Kinase Adenosine Triphosphate KAMELJIT KALSI, JOSÉ GONZÁLEZ-ALONSO Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, UK Synonyms Adenosine triphosphoric acid; Nucleotide Definition is an adenosine-derived nucleotide, ▶ ATP C10H16N5O13P3, that has a dual role as an ▶ energy source and a ▶ signaling molecule recognized by ▶ purinergic receptors. It contains high energy phosphate bonds and is used to transfer energy to cells for biochemical processes, including muscle contraction and enzymatic metabolism, through its hydrolysis to its diphosphate, ADP. ATP is hydrolyzed to its monophosphate, AMP, when it is incorporated into DNA or RNA. Basic Mechanisms The role of ATP as a direct energy source for biological systems was first proposed by Lipmann and Kalckar in 1941. Earlier experiments had shown that there was a decline in phosphocreatine (▶ PCr) levels with muscle contraction. It was therefore believed that PCr played this role. It was not until the 1960s when it was discovered that the high energy phosphate bond of PCr is first transferred into ATP before it could be utilized in biochemical reactions requiring energy. ATP is first generated by the glycolytic pathway in the cytoplasm outside the mitochondria where glucose is converted to pyruvate by the process of anaerobic metabolism. The majority of ATP is formed within the mitochondria by the second pathway known as the citric acid cycle or Kreb’s cycle by the oxidation of pyruvic acid to carbon dioxide. Coupled to this is the third method of generating ATP from the electron transport chain found on the inner mitochondrial membrane, where the efflux of protons from the mitochondrial matrix creates an electrochemical gradient (proton gradient). This gradient is used by the FOF1 ATP synthase complex to make ATP via oxidative phosphorylation [1]. During exercise, the mechanism of muscle contraction involves the contractile proteins actin which combines with myosin and ATP to produce force, ADP, and inorganic phosphate (Pi), a phenomenon known as the “Cross Bridge Cycle.” Evidence provided from protein crystallography and electron microscopy proposes a model whereby ATP causes a conformational change in the actin-binding site for myosin resulting in movement of the muscle fibers. A constant source of ATP relies on the availability of substrates for oxidation mainly in the form of muscle glycogen, blood glucose, and free fatty acids. The use of these various substrates depends on the intensity and duration of the exercise but would also be influenced by the training and nutritional status before and during exercise. Inadequate ATP production in patients with mitochondrial myopathy predisposes the individual to increased incidence of myalgia, fatigue, dyspnea, and muscular cramping during exercise [2]. ATP can also be synthesized by precursors within the body by the de novo and salvage pathways. The major site for purine synthesis is in the liver; however, these pathways are energy consuming. In contrast, the exercising muscle triggers the purine nucleotide cycle which synthesizes AMP from inosine monophosphate (IMP), a by-product of this cycle is the generation of fumarate an essential substrate for the Kreb’s cycle and hence the regeneration of more ATPs. ATP also has important roles outside of the cell acting as an extracellular signaling molecule by activating specific ATP receptors on cells lining the arteries, nerve endings, and various organs. As a result, extracellular ATP regulates many physiological responses including vascular, heart, and skeletal muscle functions. In the vasculature it has been proposed that the erythrocyte releases ATP out the cell as a response to stimuli such as low oxygen, mechanical deformation, changes in pH [3], and more recently demonstrated by increasing physiological temperatures. The mechanism by which ATP leaves the ▶ erythrocytes remains contentious, but inhibitor studies have described a regulatory role for the membrane bound ion transporter cystic fibrosis transmembrane regulator (▶ CFTR), a member of the ATP-binding cassette proteins (ABC-proteins). Adenosine Triphosphate 18 A Exercise ATP infusion 16 A Cardiac output (l min−1) 14 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 9 10 Leg blood flow (l min−1) Adenosine Triphosphate. Fig. 1 Cardiac output and leg blood flow changes with incremental exercise and graded intrafemoral artery ATP infusion (Adapted from González-Alonso (2008)) ATP is a potent ▶ vasodilator when infused in intact humans or when infused locally in vessel preparations. To demonstrate the influence of ATP on the regulation of ▶ blood flow in humans, intra-luminal infusion of ATP produces an increase in flow similar to levels found with exercise hyperemia (7–8 L min 1 from resting values of 0.5 L min 1) (Fig. 1) [4]. This is due to the interaction of ATP with the endothelium P2y receptors triggering the release of nitric oxide (NO), endothelium-derived hyperpolarization factor (EDHF), and prostaglandins mostly prostacyclin (PGI2) as well as non-NO, non-prostacyclin induced vasodilation [5] (Fig. 2). Yet again, ATP is also known to act as a sympathetic neurotransmitter where it activates P2x receptors on the vascular smooth muscle causing vasoconstriction. Thus, circulatory and interstitial ATP is essential in regulating and controlling blood flow in exercising and nonexercising limbs. Exercise Intervention To improve exercise performance, the key requirements are the exercise regimen and proper nutrition. Access to a continuous supply of ATP for energy is of continual interest in the sporting world. However, most legal sports supplements do not improve exercise performance except for three legal supplements creatine, carnitine, and sodium bicarbonate. Increasing the intake of 19 creatine enhances the levels of creatine and PCr in the muscle and provides a good reserve of high energy phosphates for ATP regeneration. Carnitine supplementation should in principle augment the oxidation of fats by the mitochondria; however, the benefits have been inconclusive. Lastly, sodium bicarbonate reduces the acidosis associated with exercise, but again the results have been varied and some negative effects have been described. Another key regulator at the center of muscle bioenergetics is the enzyme AMPK (AMP-kinase) which is activated when ATP is used for energy and the by-product AMP is formed. Activation of AMPK by AMP generates more ATP, but is also involved in lowering blood sugar, sensitizing cells to insulin, and suppressing inflammation. All of these benefits are stimulated with exercise itself and research into drugs that simulate this response is emerging. A drug that mimics AMP, AICAR (aminoimidazole carboxamide ribonucleotide) combined with a gene activating drug GW1516 is currently been tested with promising results such that they have been included on the prohibited list by the World AntiDoping Agency. The best method of stimulating ATP synthesis in skeletal muscle is by increasing the frequency and intensity of exercise. This is proven by studies using 31P magnetic resonance spectroscopy where they demonstrate an increase in ATP synthase flux and an increase in the rate 20 A Adenosine Triphosphate CFTR Stimuli HbO2 saturation PO2 PKA AC Gi pH cAMP ATP RBC deformation Blood vessel Temperature ATP P2y L-Arg Smooth Muscle COX-1 eNOS Endothelium NO PGI2 P2x AA CYP450 EDHF IP cGMP cAMP KCa KATP Adenosine Triphosphate. Fig. 2 Mechanism of ATP release from erythrocytes and ATP-mediated vasodilatation. ATP is released from erythrocytes which interact with the endothelium by releasing vasoactive mediators which stimulate vasodilation of the smooth muscle lining the vessel walls. List of abbreviations: Gi, heterotrimeric G protein; AC, adenylyl cyclase; cAMP, 3’5’adenosine monophosphate; PKA, protein kinase A; CFTR, cystic fibrosis transmembrane conductance regulator; P2y and P2x, purinergic receptor subtypes; NO, nitric oxide; eNOS, endothelial NO synthase; COX-1, cyclooxygenase-1; CYP450, cytochrome P450; L-Arg, L-arginine; PGI2, prostacyclin; AA, arachidonic acid; EDHF, endothelium-derived hyperpolarizing factor; IP, prostacyclin receptor; KCa, calcium sensitive K+ channel; KATP, ATP-sensitive K+ channel. of PCr recovery. Endurance training is accompanied by a number of physiological adaptations that include improvements in oxidative metabolism, increased capillary density and glycogen storage, and enhanced insulin sensitivity. But the most apparent change is the increased number of mitochondria within the muscle. This ensures that there is an adequate production of ATP for muscle contraction during exercise and reduction in the incidence of early fatigue. Since ATP can regulate blood flow, enhancing ATP release from erythrocytes may aid patients with vascular disease, heart failure, COPD, or spinal cord injury that are unable to participate in physical activity to a level that would improve circulation to the peripheral limbs. In this way, increasing blood flow could deliver more oxygen and nutrients to the muscle. Currently, there does not seem to be a good pharmacological alternative for improving circulation in these patients. Promoting the release of ATP from red blood cells, that is, with heat, could elicit blood flow changes that would be beneficial to patient populations is an attractive nonpharmacological remedy [6]. References 1. 2. 3. 4. 5. 6. Baker JS, McCormick MC, Robergs RA (2010) Interaction among skeletal muscle metabolic energy systems during intense exercise. J Nutr Metab 2010:905612 Testa M, Navazio FM, Neugebauer J (2005) Recognition, diagnosis, and treatment of mitochondrial myopathies in endurance athletes. Curr Sports Med Rep 4(5):282–287 Ellsworth ML et al (2009) Erythrocytes: oxygen sensors and modulators of vascular tone. Physiology (Bethesda) 24:107–116 González-Alonso J et al (2008) Haemodynamic responses to exercise, ATP infusion and thigh compression in humans: insight into the role of muscle mechanisms on cardiovascular function. J Physiol 586(9):2405–2417 Mortensen SP et al (2009) ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine. Am J Physiol Regul Integr Comp Physiol 296(4): R1140–R1148 Kalsi KK, González-Alonso J (2010) Temperature-dependent release of ATP from human erythrocytes: mechanism for the control of local tissue perfusion. Circ 122:A13005 Adipose-Tissue-Derived Hormones Adenosine Triphosphate–Binding Cassette A1 (ABCA1) Is the membrane-bound enzyme responsible for transfer of cholesterol from peripheral cells to apoA1/immature HDL in the first step of reverse cholesterol transport. This enzyme and others are upregulated by exercise. Adenosine Triphosphoric Acid A Adipokines Adipokines (also called adipocytolines) are polypeptides that are secreted from and/or produced by the adipocytes. They include leptin, adiponectin, resistin, and many cytokines of the immune system, such as tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and complement factor D (also known as adipsin). They have potent autocrine, paracrine, and endocrine functions. Cross-References ▶ Adipose-Tissue-Derived Hormones ▶ Adenosine Triphosphate Adiponectin Adherence (Regimen Adherence) The change in behavior in comparison to the prescribed regimen, sometimes suggesting making the changes due to an internal desire to change. Cross-References ▶ Behavioral Changes Adhesion Molecules They are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion. The increase of these molecules is used as a signal of cardiovascular disease risk. Adipocytokines ▶ Adipose-Tissue-Derived Hormones ▶ Adipokines Adiponectin is produced largely by the adipocyte, and like leptin, has effects on numerous metabolic parameters including glucose and lipid metabolism. However, the effects of adiponectin on appetite/food intake are not nearly as pronounced as that of leptin. In contrast to leptin, circulating adiponectin concentrations generally decrease in obesity. Resistance of tissues such as liver and muscle to adiponectin also seems to occur in obesity. Adipose Tissue Adipose tissue includes adipocytes, along with other associated tissues such as connective tissue, vascular supply, as well as other infiltrating cells such as macrophages. Adipose tissue has classically been considered as a storage depot, but is now well recognized as having an important endocrine role. Adipose-Tissue-Derived Hormones DAVID J. DYCK, LINDSAY E. ROBINSON, DAVID C. WRIGHT Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada Adipogenesis Is the process of cell differentiation by which preadipocytes become adipocytes. Synonyms Adipocytokines; Adipokines; Cytokines 21 A 22 A Adipose-Tissue-Derived Hormones Definition Cytokines are defined as cell-to-cell signaling proteins (or peptides) that confer an immunomodulatory effect. Adipocytokines (usually abbreviated as adipokines) were first defined as cytokines specifically produced and secreted by adipocytes. However, this definition of adipokines is generally considered to be insufficient as many proteins that were originally defined as such, e.g., leptin and adiponectin, are now known to be produced by adipocytes as well as other cells within adipose tissue. Other so-called adipokines such as resistin may in fact not be secreted by adipocytes at all (at least in humans), but rather by macrophages that have infiltrated adipose tissue. In this regard, adipokines might better be defined as proteins that are secreted by adipose tissue, which would include adipocytes along with the associated connective tissue, vasculature, and immune cells such as macrophages. Even so, numerous proteins currently defined as adipokines, such as leptin, adiponectin, and chemerin, are also produced within unrelated tissues such as skeletal muscle, placenta, bone, etc., further complicating the definition of adipokines. Furthermore, many proteins originally classified as adipokines (leptin, adiponectin, resistin) were not known to have an immunomodulatory role, although in some cases this has been later identified. Nonetheless, despite the imprecision with its definition, the term “adipokines” generally refers to the collection of well over 100 identified proteins and hormones produced and secreted by adipose tissue. Basic Mechanisms Adipose tissue, an endocrine organ, produces a myriad of adipokines that contribute to various metabolic abnormalities, such as insulin resistance, a hallmark feature of obesity. Adipokines can act locally within adipose tissue itself and/or systemically, interacting with numerous peripheral tissues, including skeletal muscle, heart, liver, endothelial cells of blood vessels, other adipocytes, etc., to affect many metabolic and inflammatory processes [1]. Of the more than 100 identified adipokines, several are notably related to insulin responsiveness in skeletal muscle, including leptin, adiponectin, tumor necrosis factor-alpha (TNFa), interleukin-6 (IL-6), and apelin. Skeletal muscle is the largest sink for insulin-stimulated glucose uptake in the body and is therefore an important contributor to glucose homeostasis. Thus, the communication or “cross talk” between adipose tissue and muscle, and the role that adipokines might serve in this cross talk has been a point of considerable interest in recent years (Fig. 1). Specifically, leptin and adiponectin improve insulin response, an effect that is generally ascribed to their ability to increase fatty acid oxidation and reduce intramuscular lipid content. TNFa is a pro-inflammatory cytokine secreted from numerous cells including macrophages, adipocytes, and skeletal muscle, and has been implicated as a critical mediator of insulin resistance, particularly in relation to obesity. Perhaps, most controversial of the major adipokines associated with insulin response is IL-6. IL-6 is produced by adipocytes, immune cells, and contracting muscle and was the first identified myokine. There is evidence to implicate IL-6 both as a mediator of impaired insulin action in obesity, and also as a facilitator of increased fuel metabolism during exercise. Leptin and Adiponectin Leptin and adiponectin are generally considered to be important adipokines for the maintenance of insulin responsiveness. Certainly, their near absence in conditions such as lipoatrophy is accompanied by severe insulin resistance, as well as massive accumulations of lipid in numerous peripheral tissues (liver, muscle, etc.). Since lipid accumulation is strongly associated with insulin resistance, it is believed that leptin and adiponectin are important in the prevention of lipotoxicity and the subsequent impairment of insulin response. It is widely accepted that the ability of leptin and adiponectin to prevent or minimize lipid accumulation in tissues is achieved by their ability to stimulate AMP-activated protein kinase (AMPK) and fatty acid oxidation. However, other mechanisms including lipolysis, fatty acid uptake and trafficking are also involved, some of which do not involve AMPK. The obese condition is typically characterized by increased fatty acid uptake and accumulation, and a decline in the responsiveness to insulin in peripheral tissues such as muscle. This may in part be due to the onset of leptin and adiponectin resistance, leading to reduced protection against lipid accumulation [2]. Leptin and adiponectin resistance are evident in muscle from both rodents and humans, and have been shown to be inducible by the consumption of high-saturated fat diets in rodents. The mechanisms underlying this resistance have not been elucidated, but may in part involve an increase in suppressor of cytokine signaling (SOCS3). Feeding a diet high in polyunsaturated fatty acids delays the onset of leptin and adiponectin resistance; furthermore, including fish-oilderived long-chain omega-3 fatty acids in a high-fat diet prevents/delays the development of leptin and adiponectin resistance. The exact mechanisms underlying these fatty acid effects are unknown but might involve modulation of toll-like receptor-4 (TLR4) content and downstream inflammatory signals. However, the role of Adipose-Tissue-Derived Hormones A Skeletal Muscle Insulin Receptor A GLUT4 Oxidation Lipid accumulation Altered FA metabolism Inflammatory response Exercise Toll-like receptor 4 Fatty acid transporter Cytokine receptor Fatty acids Fatty acids Adipose AMPK, other signaling pathways? PGC-1α Mitochondrial biogenesis Altered Secretory Profile: Pro-inflammatory: Increased TNF, fatty acids; decreased adiponectin (e.g. obesity, high-fat diets) Anti-inflammatory: Decreased TNF, fatty acids; increased adiponectin (e.g. exercise) Adipose-Tissue-Derived Hormones. Fig. 1 Fatty acids, particularly saturated species, and pro-inflammatory adipokines are generally believed to induce lipid accretion, as well as an inflammatory response ultimately leading to the impairment of insulinstimulated translocation of GLUT4 (glucose transporter 4). Anti-inflammatory and insulin-sensitizing adipokines are thought to reduce lipid accumulation and protect against inflammation inflammation as a cause of leptin and adiponectin resistance has not yet been established. TNFa and IL-6 Tumor necrosis factor-a is an inflammatory cytokine that is produced by numerous tissues that include skeletal muscle and adipose tissue. However, its chief source is immune cells, such as monocytes and macrophages. TNFa concentrations in plasma, muscle, and adipose tissue are often increased in cases of insulin resistance and type 2 diabetes, although this is not always the case. Its receptors, TNFR1 and 2, are located in most tissue and are also typically elevated in obesity. The deletion of TNFa receptors in mice conveys protection against the diet-induced induction of insulin resistance. TNFa may impair insulin response through several 23 mechanisms, including (1) the stimulation of p38 mitogenactivated protein kinase (MAPK) and c-Jun-terminal kinase (JNK) leading to Ser307/312 phosphorylation and inhibition of the insulin receptor substrate-1 (IRS-1), and (2) increased formation of diacylglycerol and ceramides which are believed to impair insulin signaling through the inhibition of IRS-1 (via activation of novel PKC isoforms) and Akt. Interleukin6 (IL-6) is produced by numerous tissues in the body, including various immune cells, fibroblasts, and adipose tissue. It was also the first identified myokine and is produced by contracting muscle. There has been considerable controversy regarding the role of IL-6 as it has been shown to be proinflammatory and impair glucose tolerance (when secreted by macrophages, for example), but also promotes glucose utilization during exercise. 24 A Adipose-Tissue-Derived Hormones Apelin Apelin is a recently identified adipokine that has been reported to have a host of salutary effects on skeletal muscle and systemic carbohydrate and lipid metabolism [3]. Glucose tolerance and insulin sensitivity are reduced in apelindeficient mice whereas increasing circulating apelin levels in severely insulin-resistant mice through the use of miniosmotic pumps partially restores systemic insulin action. From a cellular perspective this effect is likely mediated through the activation of 50 AMP activated protein kinase (AMPK), an energy-sensing enzyme and master regulator of cellular metabolism that stimulates insulin-independent skeletal muscle glucose disposal, enhances insulin sensitivity, and increases fatty acid oxidation. Apelin would also appear to regulate the oxidative capacity of skeletal muscle. For example, repeated daily injections of apelin for several weeks increase mitochondrial enzyme content and activity in rat skeletal muscle. Similarly, apelin-over-expressing mice have increased skeletal muscle mitochondrial content when fed a high-fat diet relative to control animals. It is interesting to note that the effects of apelin are strikingly similar to that of exercise and would perhaps imply a role for apelin in mediating the effects of exercise on skeletal muscle metabolism. Exercise Intervention The effects of chronic exercise training as a means to improve glucose tolerance and insulin responsiveness are well characterized. While there are potentially several mechanisms that may underlie this effect, an increase in mitochondrial content leading to greater rates of fatty acid oxidation is often cited as an important contributor. However, it is also noteworthy that a single bout of exercise can improve insulin response for 12– 24 h prior to any increases in mitochondrial content or capacity to oxidize fat. Although there are numerous speculations as to the possibility that exercise might confer some of its benefits on insulin response by altering the secretion of adipokines, or by changing the sensitivity of their target tissues, this has generally been poorly documented. Leptin and Adiponectin Both the acute and chronic effects of exercise on plasma leptin and adiponectin concentrations have been examined, with inconsistent findings. In general, acute exercise can decrease circulating levels of leptin if the intensity and duration are sufficiently intense, i.e., significant energy deficit. However, the provision of sufficient calories to meet the energy needs of the exercise can prevent the decrease in leptin. Chronic exercise training has been shown to lower leptin and increase adiponectin. In the case of leptin, this seems to be largely dependent on reductions in body fat. In the absence of changes in body mass/fat, changes in leptin are generally not evident. There is recent evidence that adiponectin concentrations can be increased by intense exercise independent of changes in body fat [4]. There is also evidence based on rodent models that intense treadmill exercise can protect skeletal muscle from becoming both leptin- and adiponectinresistant during the administration of a high-fat diet. TNFa There is evidence that chronic exercise, in combination with dietary restriction, can reduce circulating TNFa concentrations. However, dietary restriction alone also reduces TNFa and other markers of inflammation, suggesting that it is the reduction in body fat that is the important factor, rather than the exercise per se. Moreover, the effect of exercise on TNFa production has largely focused on circulating immune cells. Thus, the degree to which adipose-tissue-derived TNFa is reduced is less well characterized, as is the responsiveness of peripheral tissues to TNFa following chronic exercise. Apelin Apelin, similar to adiponectin, has been shown to increase with exercise. Exercise, possibly working via catecholamines, activates AMPK in adipose tissue. In cell culture models, the pharmacological activation of AMPK with a compound called AICAR leads to increases in the expression of PPARg coactivator 1 alpha (PGC-1a), a transcriptional coactivator that controls the expression of apelin. PGC-1a also increases adipose tissue mitochondrial content, an event that is required in adiponectin synthesis and secretion. In this regard, a catecholamineAMPK-PGC-1a axis may be critical in the exercisemediated regulation of adipose tissue metabolism and adipokine profile. References 1. 2. 3. 4. Schaffler A, Scholmerich J (2010) Innate immunity and adipose tissue biology. Trends Immunol 31:228–235 Mullen KL, Pritchard J, Ritchie I, Snook LA, Chabowski A, Bonen A, Wright D, Dyck DJ (2009) Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats. Am J Physiol Regul Integr Comp Physiol 296: R243–251 Xu S, Tsao PS, Yue P (2011) Apelin and insulin resistance: another arrow for the quiver? J Diabetes 3:225–231 Garekani ET, Mohebbi H, Kraemer RR, Fathi R (2011) Exercise training intensity/volume affects plasma and tissue adiponectin concentrations in the male rat. Peptides 32:1008–1012 Adrenergic Receptors Adiposity The accumulation of adipose (fat) tissue; the state of being overweight. Cross-References A Adrenergic Receptors JAMES R. DOCHERTY Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland ▶ Obesity Synonyms Adrenoceptors; Sympathetic response mediators Adiposity Signal Hormone that circulates in the blood in proportion to the amount of fat stored in the body and which provides a signal to other organs such as the brain. A decrease in adiposity signals may elicit hyperphagia (increased energy intake) and decreases in energy expenditure, while an increase results in decreased energy intake and increased energy expenditure. Insulin and leptin are adiposity signals that are secreted primarily from the pancreas and adipose tissue, respectively. ADMA Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO-synthase. It is generated during proteolysis of methylated proteins. ADMA is removed either by renal excretion or metabolic degradation by the enzyme dimethylarginine dimethylaminohydrolase. ADMA can be produced and degraded by several cell types including human endothelial and tubular cells. Elevated ADMA concentrations in the blood are found in a number of chronic diseases associated with endothelial dysfunction such as hypercholesterolemia, hypertension, arteriosclerosis, chronic renal failure, and chronic heart failure. Adolescence A transitional stage of human development occurring between puberty and adulthood. The term adolescence includes girls aged 12–18 years and boys aged 14–18 years. Definition ▶ Adrenergic receptors are cell membrane receptors belonging to the seven transmembrane spanning G-protein-linked superfamily of receptors [1]. They respond to the sympathetic neurotransmitter noradrenaline and to the hormone adrenaline (and to various exogenous agonists) by producing a response within the cell, involving a second messenger, or ion channel. Adrenergic receptors can be divided into three major types, each with three subtypes [2, 3] (see Table 1). ▶ Alpha1-adrenergic receptors are linked to the enzyme phospholipase C (PLC), ▶ alpha2-adrenergic receptors are linked to inhibition of the enzyme adenylate cyclase (AC) and to opening of potassium (K+) channels, and ▶ beta-adrenergic receptors are linked to stimulation of AC (see Table 1). Basic Mechanisms Adrenergic receptors are classically the receptors involved in the “fight or flight” reaction, the mobilization of resources caused by activation of the sympathetic nervous system that prepares the body for bouts of severe activity. This involves the release of the hormone adrenaline from the adrenal medulla into the bloodstream and an increase in sympathetic nerve activity mediated by the neurotransmitter noradrenaline. Adrenaline and the sympathetic nerves act to cause cardiac stimulation, increasing both heart rate and force of ventricular contraction to increase cardiac output and get more blood to exercising muscle. Adrenaline acts on vascular beta2-adrenergic receptors to dilate particularly muscle arterioles to deliver more of this increased cardiac output to skeletal muscle. Adrenaline mobilizes glucose and free fatty acids as energy sources. Sympathetic activation will also cause vasoconstriction in less vital vascular beds, particularly splanchnic and skin (although the skin vasculature may dilate later to dissipate heat), to divert blood to skeletal muscle. Sympathetic activation also mobilizes blood from the reservoir in the large veins (the capacitance vessels) by veniconstriction. Adrenaline also causes bronchodilatation to aid in getting 25 A 26 A Adrenergic Receptors Adrenergic Receptors. Table 1 Subtypes of the adrenergic receptor family, important G protein and second messenger linkages (enzyme or ion channel), and major actions Subtype G protein Linkage Major actions Alpha1A Gq/11 PLC sm contraction Alpha1B Gq/11 PLC sm contraction Alpha1D Gq/11 PLC sm contraction Alpha2A Gi/o ACI/K+ Nerve inhibition/sm contraction Alpha2B Gi/o ACI/K + Nerve inhibition/sm contraction Alpha2C Gi/o ACI/K+ Nerve inhibition/sm contraction Beta1 Gs ACS Cardiac stimulation/lipolysis Beta2 Gs ACS sm dilatation/metabolic Beta3 Gs ACS sm dilatation/metabolic/cardiac inhibition ACI inhibition of enzyme adenylate cyclase, ACS stimulation of enzyme adenylate cyclase, K+ opening of potassium (K+) channels, PLC stimulation of enzyme phospholipase C, sm smooth muscle (e.g., vascular, bronchial) oxygen into the blood. Ocular effects involve alpha1adrenergic receptor mediated dilatation of the pupil, and beta-adrenergic receptor mediated paralysis of accomodation, increasing the amount of light reaching the retina and setting the lens for wider vision. Sweating is also an adrenergic response, but the neurotransmitter is acetylcholine and beyond the scope of this article. Genito-urinary actions of the adrenergic system are also important, and alpha- receptors are involved in contraction the smooth muscle of the vas deferens, in contracting the neck of the bladder and involved in prostate function. Adrenergic receptors are also present in the spinal cord and brain mediating diverse functions from control of blood pressure to mediating analgesia. We can now consider the subtypes of adrenergic receptor that mediate these many physiological actions. Alpha1-Adrenergic Receptors Alpha1-adrenergic receptors are the classical adrenergic receptors mediating smooth muscle contraction, but we do not know the exact physiological role of each of the three subtypes. Alpha1A-receptors are widespread in many smooth muscles and are activated by administered agonists, but alpha1D or alpha1B may be more important physiologically for neurotransmission. Alpha1-adrenergic receptors in the vascular system have a major role in the control of blood pressure and the response to falls in blood pressure. A fall in blood pressure due to causes such as hemorrhage will activate the baroreceptor reflex and cause sympathetic activation to vasoconstrict less vital vascular beds, especially splanchnic and skin. However, profound falls in blood pressure resulting in a decreased blood flow to the brain activates a stronger reflex due to brain ischemia. This is the CNS Ischemic Reflex which is a last-ditch reflex to maintain brain blood flow at the expense of all other vascular beds by causing widespread vasoconstriction involving alpha1adrenergic receptor activation. Another important role of vascular alpha1-adrenergic receptors is temperature control. as vasoconstriction of superficial blood vessels is an important mechanism to conserve heat. Alpha1-adrenergic receptors are also involved in the hyperthermia to amphetamine derivatives such as ▶ methylenedioxymethamphetamine (MDMA), which produces a dangerous hyperthermia in hot conditions, such as found at a “Rave.” In nonvascular smooth muscle, alpha1-adrenergic receptors mediate inhibition of micturition, but the density of alpha1-adrenergic receptors in the neck of the bladder is greater in males, suggesting a sexual function to prevent retrograde ejaculation into the bladder. Alpha1-adrenergic receptors mediate contraction of the vas deferens and seminal vesicles and have an important role in ejaculation. Alpha1-adrenergic receptor agonist mediated vasoconstriction can be used to treat hypotension, and can be used in nasal decongestion. Alpha1-adrenergic receptor agonists also act on the eye to dilate the pupil by contracting the dilator pupillae muscle, and also have actions to reduce intraocular pressure, presumably by restricting blood flow. Alpha1-adrenergic receptor antagonists lower blood pressure in hypertension and are used in the treatment of Benign prostatic hypertrophy. Alpha2-Adrenergic Receptors Like alpha1-adrenergic receptors, alpha2-adrenergic receptors are involved in vasoconstriction, but their exact role, Adrenergic Receptors and the role of each of the subtypes, in the control of blood pressure has not been fully established. They are not as widespread in the vascular system as alpha1-adrenoceptors, but they may have a role particularly on veins (possibly alpha2C-receptors) to cause veniconstriction. In addition, alpha2A-receptors on endothelial cells mediate relaxation of vascular smooth muscle. Alpha2A-adrenergic receptors are involved in the central control of blood pressure, mediating a profound fall in blood pressure, and this explains the antihypertensive actions of alpha2-receptor agonists such as clonidine. Alpha2-adrenergic receptors also mediate analgesia centrally. Alpha2-adrenergic receptors, particulary alpha2A and to a lesser extent alpha2C, are also present on the prejunctional nerve terminal of adrenergic and other nerves, where they mediate inhibition of neurotransmitter release. In adrenergic nerves, this is a negative feedback to modulate release. Although the exact importance of these receptors is unclear, there is evidence that absence of the prejunctional alpha2-adrenergic receptor in animal models increases susceptibility to heart failure, presumably by allowing excess release of noradrenaline neurotransmitter. Alpha2-adrenergic receptors on nonadrenergic nerves act to inhibit function in those nerves. Sympathetic activation inhibits the cholinergic and other nerves involved in digestion and so causes inhibition of gastrointestinal function. Beta1-Adrenergic Receptors Beta1-adrenergic receptors are the major receptors involved in cardiac stimulation. Like all beta-receptors, the main signaling pathway is by activation of the enzyme adenylate cyclase, resulting in increased levels of the second messenger cAMP (Table 1). Beta1-receptor activation depolarizes the unstable pacemaker cells of the ▶ Sinoatrial (SA) node so that the threshold for generation of action potentials is reached faster, resulting in a faster heart rate. At the ▶ atrioventricular (AV) node, betareceptor mediated depolarization allows faster conduction of the impulse from the atria to ventricles, allowing a fast atrial rate to pass from atria to ventricles. In the atrial and ventricular muscle fibers, beta1-receptor stimulation increases calcium entry during depolarization, increasing the force of contraction, thus increasing stroke volume. Cardiac output (CO) is defined as the volume of blood pumped per minute, and depends both on heart rate (HR) (per minute) and stroke volume (SV) (volume pumped per beat), by the equation: CO = HR  SV. Resting cardiac output is around 5 L/min. In exercise, we can increase cardiac output by increasing either HR or SV, or both. In A light exercise, HR tends to increase markedly, with a smaller effect on SV, but in severe exercise there are also larger increases in SV. HR may reach 200 beats/min in severe exercise in a young healthy adult, from a resting of around 70 beats/min, and stroke volume may increase from 70 to 125 ml, giving a change in CO from 5 to 25 l. Trained athletes, who may have an enlarged ventricle, will increase their CO further by increasing SV further. Cardiac transplant patients who have a functional denervation of the heart, can increase their CO by the intrinsic properties of the heart and by the actions of the hormone adrenaline. Beta1-adrenergic agonists are employed as cardiac stimulants. ▶ Beta-blockers, or beta1-adrenergic receptor antagonists, are used for a wide variety of cardiovascular indications including hypertension, angina, and even heart failure. A number of beta-adrenergic receptor antagonists exhibit partial agonism, that is, they produced some beta-adrenergic stimulation while acting mainly as antagonists. The mode of action may involve actions at two forms of the beta1-adrenergic receptor: antagonist at beta1 high affinity receptors and agonist in higher concentrations at beta1 low affinity receptors. Beta2-Adrenergic Receptors Beta2-adrenergic receptors mediate relaxation of vascular smooth muscle and the smooth muscle of the bronchus, gut, bladder, urethra, uterus, etc. Beta-2 adrenergic receptors are generally thought to be non-innervated receptors, far from nerve endings, acting as targets for circulating adrenaline since noradrenaline is a poor agonist at these receptors. In the vascular system, beta2-adrenergic receptors are the main mediators of adrenergic relaxation, acting to stimulate the enzyme adenylate cyclase and increase cAMP production, although all beta-receptor subtypes mediate relaxation. Interestingly, in the coronary artery, relaxation is mediated by the beta1-receptor, perhaps allowing nerve-released noradrenaline to dilate these crucial arteries. Beta-adrenergic receptor mediated relaxation of the vascular system can be direct by actions on the smooth muscle or indirect by causing release of nitric oxide from the endothelium. Another important site of beta2-adrenoceptor relaxation is bronchial smooth muscle and beta2-adrenergic agonists are widely used in asthma as bronchodilators. Beta3-Adrenergic Receptors The Beta3 is a controversial beta-adrenergic receptor, with difficulties in positive identification due to lack of truly selective antagonist drugs. Beta3-adrenergic receptors, like beta2- and even beta1-, are involved in metabolic effects, 27 A 28 A Adrenoceptors particularly lipolysis in adipose tissue. Beta3-adrenergic receptors also mediate smooth muscle relaxation of vascular and nonvascular smooth muscle, and may be particularly important in the bladder. The most surprising effect mediated by beta3-adrenergic receptors is an action to decrease myocardial contractility by stimulation of nitric oxide synthase in cardiac muscle cells to produce nitric oxide, and this may be a protective mechanism to prevent overstimulation of the heart by the adrenergic system as these receptors would be activated by high concentrations of noradrenaline and adrenaline to partly counteract their beta1-mediated stimulant actions. Exercise Intervention stimulation) but less chronic desensitization of adrenergic receptors, as the exposure time to elevated catecholamines is reduced, resulting in a training related increase in adrenergic responsiveness. References 1. 2. 3. 4. 5. Adrenergic Drugs and Sport The beta2-adrenergic receptor is the main beta-adrenergic receptor targeted in sport since beta2-adrenergic receptor activation has bronchodilator and anabolic actions [4]. A large number of athletes are classed as asthmatic, perhaps caused by continual exposure to allergens and to cold air in winter. Inhaled beta2-adrenergic receptor agonists have been reported to be effective against exercise-induced bronchospasm. Beta2-adrenergic receptor agonists also have growth promoting (anabolic) actions to improve muscle regeneration and function after injury. A second class of adrenergic agents relevant in sport belong to the class of stimulants. Stimulants are banned only in competition, as any advantage would be transient, and a total ban would be difficult since many over the counter medicines contain stimulants [5]. For example, nasal decongestants are alpha1-adrenergic receptor agonists which produce vasoconstriction of the nasal mucosa, reducing mucosal swelling, and mucosal mass to reduce congestion [5]. Stimulants that have actions centrally in the brain would be likely to increase alertness or increase motivation, and those with beta1-adrenoceptor actions would produce cardiac stimulant effects. For these reasons, most stimulants are banned in competition. 6. 7. Alexander SP, Mathie A, Peters JA (2008) Guide to receptors and channels (GRAC). Br J Pharmacol 153(Suppl 2):S1–S209 3rd edition Docherty JR (1998) Subtypes of functional alpha1- and alpha2adrenoceptors. Eur J Pharmacol 361(1):1–15 Guimarães S, Moura D (2001) Vascular adrenoceptors: an update. Pharmacol Rev 53(2):319–356 Davis E, Loiacono R, Summers RJ (2008) The rush to adrenaline: drugs in sport acting on the beta-adrenergic system. Br J Pharmacol 154(3):584–597 Docherty JR (2008) Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). Br J Pharmacol 154(3):606–622 Zouhal H, Jacob C, Delamarche P, Gratas-Delamarche A (2008) Catecholamines and the effects of exercise, training and gender. Sports Med 38(5):401–423 Bracken RM, Brooks S (2010) Plasma catecholamine and nephrine responses following 7 weeks of sprint cycle training. Amino Acids 38(5):1351–1359 Adrenoceptors ▶ Adrenergic Receptors Adult Hippocampal Neurogenesis It consists of the generation of new neurons in the adult brain, specifically, the neurons born during adult life in the subgranular zone of the hippocampal dentate gyrus (generating granule neurons that populate the granule cell layer). These neurons differentiate into mature neurons becoming integrated in adult networks. They may play roles both during differentiation and after maturation. Training and Adrenergic Responses Training may increase an athlete’s ability to release ▶ catecholamines from the adrenal medulla during bouts of exercise [6]. Although increased release of catecholamines in exercise might be predicted to cause downregulation of adrenergic receptors and so largely counteract the effects of increased release, there is evidence that training may also result in increased metabolism of catecholamines [7]. Hence, a greater release coupled with a more rapid metabolism of catecholamines would allow increased acute response to catecholamines (for instance, cardiac Aerobic Activity Aerobic activity is any form of rhythmic muscular activity where the cardio-respiratory system is able to supply sufficient oxygen to meet metabolic demand without the accumulation of significant quantities of lactate. If the intent is to use such aerobic activity to maintain cardiovascular health, sufficient of the large body muscles must Aerobic Metabolism be activated to use 50–70% of the individual’s maximal oxygen consumption (for example, by jogging, treadmill running or exercising on a cycle ergometer). _ 2 max ) Aerobic Capacity (VO The maximal amount of oxygen that can be consumed and utilized per time unit. Cross-References _ 2 max ) ▶ Maximal Oxygen Update (VO A Aerobic Metabolism ANTONIOS MATSAKAS1, KETAN PATEL2 1 Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA 2 School of Biological Sciences, University of Reading, Whiteknights, Reading, UK Synonyms Aerobic energy system; Aerobic respiration; Cellular oxidation; Oxidative metabolism; Oxygen system Definition Aerobic Endurance Aerobic endurance represents the capacity to sustain a high fraction of maximal oxygen consumption through the entire effort duration. It is mainly determined by oxidative enzymes activity and muscle fiber composition. Aerobic Energy System ▶ Aerobic Metabolism Aerobic Exercise Energy Expenditure Exercise energy demands that are met by aerobic metabolism and measured as the amount or rate of O2 consumed. Metabolism is defined as the sum of chemical reactions taking place in a live organism to maintain life. Aerobic means oxygen dependent and aerobic metabolism refers to an energy-generating system under the presence of oxygen as opposed to anaerobic, i.e., oxygen independent metabolism. Aerobic metabolism uses oxygen as the final electron acceptor in the electron transport chain and combines with hydrogen to form water [1]. In essence, the vast majority of adenosine triphosphate (ATP) synthesis takes place via aerobic breakdown of energy substrates through the coupling of respiratory chain and oxidative phosphorylation. Aerobic metabolism includes in terms of energy sources carbohydrates and lipids and to a less extent proteins. In exercise, aerobic metabolism predominates supplying a large amount of energy at low power during exercise exceeding 1 min in duration regardless of intensity (e.g., the 800 m run and upward, the 200 m swim and upward; [2]). In terms of enzymes, aerobic metabolism includes pyruvate dehydrogenase, the enzymes of lipolysis, fatty acid degradation, the citric acid cycle, and the electron transport chain and the ATP synthase. Characteristics Aerobic Fitness The ability to deliver oxygen to the exercising muscles and to utilize it to generate energy during exercise. Cross-References ▶ Aerobic Power, Tests of Aerobic Glycolysis The catabolism of glucose or glycogen to CO2 and H2O. Dietary macronutrients containing carbohydrates, fats, and proteins are biochemically processed to give rise to cellular energy substrates such as glucose, fatty acids and glycerol, as well as amino acids. The different metabolic pathways of glucose, fatty acid, and protein catabolism are integrated in the form of acetyl coenzyme A (coA) in the mitochondria. Glucose is broken down to pyruvate through the anaerobic process of glycolysis and enters the mitochondria where it is converted to acetyl coA and cellular energy is generated in the citric acid cycle, electron transport chain, and oxidative phosphorylation via the removal and transfer to oxygen of energy-rich electrons (Fig. 1). 29 A 30 A Aerobic Metabolism Energy substrates (lipids, carbohydrates, proteins) cytoplasm glucose fatty acids amino acids O2 coenzyme A Inner mitochondrial membrane 2e− on ctr t ele spor n tra hain c tive n da atio oxi oryl ph os ph ADP + Pi Acetyl coA H2O H+ NADH FADH2 Citric Acid cycle ATP CO2 Inner compartment Aerobic Metabolism. Fig. 1 Schematic overview of aerobic metabolism. Acetyl coenzyme A, the activated carrier that transfers the acetyl group into the citric acid cycle, interconnects the metabolic pathways of lipid, carbohydrate, and protein catabolism. A significant amount of energy can be generated during aerobic metabolism by means of citric acid cycle, electron transport chain, and oxidative phosphorylation during light to moderate endurance exercise There are two major electron carriers in the oxidation of substrates that provide energy-rich molecules by carrying electrons with a high energy-transfer potential: the nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD). NAD is derived from niacin and FAD is derived from riboflavin, both are members of the vitamin B family. In the substrate oxidation two protons (H+) and electrons are removed. NAD+ receives the two electrons and one H+ (the other H+ is carried in the cell fluid), while FAD accepts both the H+ and electrons are reduced to NADH and H+ (NADH.H+) and FADH2, respectively. Acetyl coenzyme A, the common intermediate compound in carbohydrate, lipid and protein breakdown releases carbon dioxide and for one CO2 removed one NAD+ is reduced. The gaining of electrons known as the process of reduction aims at capturing most of the substrate energy, which can be further transferred to oxygen and thus release energy that can be used to phosphorylate ADP and give rise to ATP. Oxidation of one glucose in muscle yields six CO2, four ATP, eight NADH, and four FADH2. NADH and FADH2 are oxidized in electron transport chain by oxygen providing the energy for ATP synthesis in oxidative phosphorylation. Thus the net energy Aerobic Metabolism. Table 1 Energy amount in aerobic metabolism Net energy (ATP) yield from glucose oxidation Blood glucose Glycolysis 2 Citric acid cycle 2 Electron transport chain 26 Total 30a a Assumption: Based on more recent calculations the oxidation of 1 mol of NADH.H+ or FADH2 produces 2.5 or 1.5 ATP, respectively (although in older textbooks the energetic yields for NADH.H+ and FADH2 are traditionally reported as 3 and 2 ATP, respectively) yield in ATP from glucose oxidation through pyruvate oxidation, the citric acid cycle, the electron transport chain, and oxidative phosphorylation is 30 ATP (Table 1). In addition, fatty acids represent a significant source of energy in light and moderate-intensity exercise stimuli. However, since the rate of ATP resynthesis through the oxidation of fatty acids derived from either the myocellular triacylglycerol depots or the adipose tissue Aerobic Metabolism is relatively low (0.2–0.3 mmol/kg/s), they cannot support hard exercise. Exercise is known to accelerate the glycolysis (the breakdown of glucose to pyruvate), pyruvate oxidation, lipolysis (the breakdown of triacylglycerols), fatty acid oxidation, citric acid cycle, and the oxidative phosphorylation in skeletal muscle [2]. Measurements/Diagnostics A product of anaerobic metabolism, the lactate, can be useful in estimating aerobic endurance and indirectly aerobic metabolism, since there is a strong relationship between performance in endurance events and the moderate exercise intensity corresponding to a given blood lactate concentration. Thus, the higher endurance performance, the lower the blood lactate concentration. Higher endurance performance indicative of higher aerobic metabolism capacity can be developed through exercise. A plot of blood lactate concentration versus exercise intensity for an untrained individual shifts to the right as a consequence of training adaptation. Therefore an untrained individual will produce more lactate for a given intensity of exercise compared to a trained individual (Fig 2a). Exercise intensities that maintain blood lactate levels below 4 mmol/L are considered the most effective for improvements in aerobic metabolism, cardiovascular system, and lipidemic profile. At the histological level, succinate dehydrogenase activity (SDH) is another useful indicator of mitochondrial oxidative potential reflecting the metabolic properties of the cell. Slow- and fast-twitch muscle fibers have high and low SDH activity, respectively, and can be identified on a muscle section (Fig. 2b). Skeletal muscle fiber SDH activity can be modulated by regular endurance exercise [3]. Blood lactate (mmol/L) a 14 12 Untrained Trained A Regular endurance exercise promotes aerobic metabolism and has been considered to be beneficial in both health and disease triggering the transition of skeletal muscle toward an oxidative phenotype by regulating slow-twitch contractile machinery, mitochondrial biogenesis, and fatty acid oxidation. Such remodeling of the skeletal muscle is brought about by a wide signaling network of transcriptional regulators that boost aerobic metabolism. An overview of power metabolic regulators and their downstream targets are summarized in Table 2. In brief, peroxisome-proliferator-activated receptor d (PPARd) is a member of the nuclear receptor super-family of transcriptional regulators that has been shown to regulate oxidative metabolism and slow-twitch fiber phenotype. AMP-activated protein kinase (AMPK) is a cellular energy sensor that is activated robustly in skeletal muscle by both acute and chronic exercise boosting muscle transcriptional activity and inducing aerobic metabolism. Sirtuins are known to regulate cell differentiation, metabolism and inflammation. Silent information regulator two protein 1 (SIRT1) is the most extensively studied sirtuin and is expressed predominantly in oxidative slow-twitch muscle. SIRT1 induces oxidative genes and mitochondrial biogenesis in skeletal muscle, leading to an increase in oxygen consumption, running endurance, and protection against metabolic diseases. Peroxisome-proliferatoractivated receptor g coactivator-1 alpha (PGC-1a) is a well-characterized transcriptional coactivator that regulates a fast-to-slow muscle fiber shift leading to an improved aerobic metabolism. Recent interest has emerged for pharmacological targeting of such key molecules that stimulate aerobic metabolism mimicking exercise-mediated changes and exhibiting potential therapeutic effects against metabolic disorders [4]. b 10 8 6 4 2 Exercise intensity Aerobic Metabolism. Fig. 2 Examples of measurements for aerobic metabolism. (a) Estimation of aerobic capacity by using the lactate-intensity plot, (b) SDH activity of skeletal muscle; 1 and 2: muscle fibers with high and low SDH activity, respectively 31 A 32 A Aerobic Power, Tests of Aerobic Metabolism. Table 2 Powerful metabolic regulators of aerobic metabolism and their gene targets in skeletal muscle (Due to space limitations references have been omitted) PPARd PGC-1a AMPK SIRT1 Fatty acid oxidation: HFBP, FAT/ CD36, m-CPT1, PDK4, HMGCS2, thiolase, LCAD Fatty acid oxidation: m-CPT1 Fatty acid oxidation: PPARd, PDK4, SCD1 Fatty acid oxidation: MCAD, PDK4, FAT/CD36 Oxidative metabolism: Succinate dehydrogenase, citrate synthase Oxidative metabolism: Nrf1, ERRg Oxidative metabolism: PPARd, FASN, SCD1 Oxidative metabolism: NDUFB8, CoxVa Mitochondrial respiration and thermogenesis: Cytochrome C, cytochrome oxidase II/IV, UCP-2/3, PGC-1a Mitochondrial respiration and thermogenesis: Cytochrome C, cytochrome oxidase II and IV, UCP2/3, Nrf1 Mitochondrial respiration and thermogenesis: PPARd, PGC-1a Mitochondrial biogenesis: PPARs(a/g/d/PGC-1a), ERRa, Nrip1, Tfam, Nrf1, UCP3 Fiber type shift: Myoglobin, troponin I slow Slow-twitch fiber program: Myoglobin, troponin I slow, Mef2 Fiber type shift: PPARd Fiber type shift: PGC-1a, Myoglobin, troponins Energy expenditure: NAD+, SIRT1 Energy metabolism: PGC1a/b, FOXO 1/3, ERRa, Nrip1 ATP5G3 AMPK AMP-activated protein kinase; ATP5G3 ATP synthase, H + transporting, mitochondrial F0 complex, subunit C3; CoxVa cytochrome c oxidase subunit V; ERRa/g estrogen related receptor a/g; FASN fatty acid synthase; FAT/CD36 fatty acid translocase protein/(CD36); FOXO Forkhead box class O; H-FABP Heart fatty acid-binding protein; HFBP high-affinity folate-binding protein; HMGCS2 3-hydroxy-3-methylglutaryl coenzyme A synthase; LCAD long-chain acyl-coenzyme A dehydrogenase; MCAD Medium-chain acyl-coenzyme A dehydrogenase; m-CPT1 muscle carnitine palmitoyltransferase 1; Mef2 myocyte enhancer factor-2; NAD+ Nicotinamide Adenine Dinucleotide; NDUFB8 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8; Nrf1 Nuclear respiratory factor 1; Nrip 1 Nuclear receptor interacting protein 1; PDK4 pyruvate dehydrogenase kinase 4; PGC-1a peroxisome-proliferator-activated receptor g coactivator 1a; PPARd peroxisome-proliferator-activated receptor d; SCD1 stearoyl-CoA desaturase 1; SIRT1 Silent information regulator two protein 1; Tfam transcription factor A, mitochondrial; UCP-2/3 uncoupling protein-2/3 References Definition 1. Aerobic power, otherwise known as maximal O2 con_ 2 max ), can be defined as the maximal rate sumption (VO at which O2 can be consumed during whole body exercise _ 2 max is the at sea level. According to the Fick equation, VO _ product of ▶ cardiac output (Q) and the arteriovenous O2 content difference (Ca O2 Cv O2 ): 2. 3. 4. McArdle WD, Katch FI, Katch VL (2007) Exercise physiology: energy, nutrition and human performance. Lippincott Williams and Wilkins, Baltimore Mougios V (2006) Exercise biochemistry. Human Kinetics, Champaign Matsakas A, Mouisel E, Amthor H, Patel K (2010) Myostatin knockout mice increase oxidative muscle phenotype as an adaptive response to exercise. J Muscle Res Cell Motil 31:111–1125 Matsakas A, Narkar V (2010) Endurance exercise mimetics in skeletal muscle. Curr Sports Med Rep 9:227–232 Aerobic Power, Tests of ALAN R. BARKER, NEIL ARMSTRONG Children’s Health and Exercise Research Centre, Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK Synonyms Aerobic fitness; Cardiorespiratory fitness; Maximal aerobic power; Maximal O2 uptake; Peak O2 uptake _
ðCa O2 _ 2¼Q VO Cv O2 Þ _ is the product of heart rate and ▶ stroke volume. where Q _ 2 max using cardiac As the direct determination of VO catheterization combined with serial arterial and venous blood samples is highly invasive, its use in humans is limited for specific research purposes only. Consequently, _ 2 max is routinely measured using indirect whole body VO calorimetry based on respiratory measurements of the volume of expired air and its fractional O2 content. This is performed using either the classical Douglas bag tech_ 2 sample every 30–60 s, or on nique providing a VO a breath-by-breath basis using an automated gas analysis system. However, due to the presence of large inter-breath _ 2 during exercise in humans, the fluctuations in VO Aerobic Power, Tests of breath-by-breath response is typically averaged over _ 2 max . 10–30 s to establish VO Based on the physiological determinants of the Fick _ 2 max can be viewed as the functional upper equation, VO limit for the cardiovascular, pulmonary, and muscular systems to transport and utilize O2 during exercise. Since its original description in 1923 by the Nobel Laureate A.V. _ 2 max has become one of the most Hill and colleagues, VO measured variables in exercise physiology and is widely considered as the best single measure of cardiorespiratory _ 2 max is known to reduce fitness. For example, a high VO the risk of all-cause mortality and cardiovascular disease in adults and is considered a prerequisite for successful endurance performance in elite athletes. Description _ 2 max requires that during The traditional paradigm for VO _ 2 will no longer progressive exercise to exhaustion, VO increase linearly with increasing exercise intensity, but _ 2 fails to display a plateau (Fig. 1). Therefore, if VO increase by a predetermined amount despite an increase _ 2 max is achieved. In in exercise intensity, a valid VO practice, however, only 20–50% of adults and children _ 2 plateau performing exhaustive exercise display a VO 3.50 3.00 VO2 (L·min−1) 2.50 2.00 A _ 2 (VO _ 2 peak ) is more appropriate [3, 4]. The term peak VO _ here, reflecting the highest VO2 obtained during an exercise test to exhaustion in the absence of a plateau. _ 2 plaDue to the failure to consistently observe a VO teau during exhaustive exercise, secondary criteria are _ 2 max . These include the measureoften used to verify a VO ment of heart rate and ▶ respiratory exchange ratio at exhaustion, and the assessment of post-exercise blood lactate accumulation. While there is no universal agreement for which set of criteria (or single criterion) and the specific cutoff values that should be used, they remain _ 2 max [4]. However, commonplace when measuring VO recent research has shown that secondary criteria produce _ 2 max by up to 30% in some cases, a significantly lower VO _ 2 max, during cycling exercise or falsely reject a “true” VO [3]. The authors cautioned against using secondary criteria and championed the use of a supramaximal exercise bout to exhaustion following the initial incremental _ 2 max test to confirm the measurement of a “true” VO _ (Fig. 2). By plotting the composite VO2 profile from _ 2 plaboth tests (incremental and supramaximal), the VO teau criterion can be obtained within a single testing session despite the absence of a plateau during the initial incremental test in the majority of cases. If the highest _ 2 during the supramaximal exercise bout is greater VO than a predetermined amount (usually the within_ 2 max ), say 5%, then participant reproducibility for VO the supramaximal bout will need to be repeated at a higher exercise intensity following a short rest. This _ 2 is less than 5%. will be repeated until the increase in VO _ The highest VO2 across the incremental and supramaximal tests is then taken as the participant’s _ 2 max . VO 1.50 Clinical Use/Application 1.00 Maximal Exercise Testing 0.50 0.00 0 50 100 150 200 250 Power output (W) 300 350 _ 2 response during Aerobic Power, Tests of. Fig. 1 The VO incremental cycling exercise using a ramp rate of 25 W min 1 in a healthy adult female. The solid line represents a simple linear regression that was plotted between 75 and 250 W and extrapolated to end exercise (denoted by the dotted line). The _ 2 from that expected based departure (250 mL min 1) in VO _ 2 -power output relationship indicates on the submaximal VO _ 2 plateau in this participant a clear VO _ 2 max is the The most widely used protocol to measure VO progressive incremental test to exhaustion, otherwise known as the graded exercise test. Such tests are extremely powerful in profiling an individual’s ▶ aerobic fitness, as _ 2 max , “submaximal” in addition to determining VO parameters of aerobic function (e.g., O2 cost of exercise, ▶ blood lactate threshold) can be obtained (see [5] for further discussion). Such tests are routinely performed on a cycle ergometer or motorized treadmill. Although _ 2 max is typically 5–10% higher during treadmill runVO ning and treadmill exercise allows for a more common form of physiological stress (e.g., walking, jogging), it does not permit accurate quantification of power output, unlike cycling. When testing athletes or sport performers, 33 A 34 A Aerobic Power, Tests of _ 2 max in a 9 -year-old Aerobic Power, Tests of. Fig. 2 A combined ramp incremental and supramaximal cycle test to establish VO boy. The protocol is shown in A where a 10 W min 1 increment was used for the ramp test, and following a 15 min of recovery, _ 2 response is shown in B. The a supramaximal bout to exhaustion at 105% of the ramp test peak power was used. The resultant VO _ 2 from the ramp test was 1.65 L min 1. Despite the increase in power output during the supramaximal bout, the highest VO _ 2 plateau. The child’s VO _ 2 max was taken to be _ 2 recorded was 1.57 L min 1, indicating the achievement of a VO highest VO 1.65 L min 1. The vertical dotted lines represent the start and end of the incremental and supramaximal bouts _ 2 max on a sporthowever, it is important to establish VO specific ergometer to monitor their modality-specific training adaptations and maximize training prescription. _ 2 max are The choice of testing protocols to establish VO numerous and vary on whether the increments in exercise intensity (e.g., power output, running speed, and/or gradient) are made continuously or discontinuously (each stage is separated with a 1–10 min rest), or in a ramp or stepwise function (Fig. 3). Studies have shown no differ_ 2 max between continuous and discontinuous ences in VO protocols, or protocols employing either a ramp function or 1–3 min step increments. However, due to the shorter test duration and the avoidance of large increments in exercise intensity, which may result in premature fatigue especially in participants with low fitness and physical activity levels, there is increasing popularity toward using continuous incremental protocols employing either a ramp or 1 min step increments in exercise intensity [1, 5]. If steady-state conditions are required to quantify physiological variables in relation to exercise intensity though (e.g., O2 cost of exercise), longer stage durations of 3 min may be required. For cycle ergometry the protocol usually begins with a brief period of unloaded or very light pedaling Aerobic Power, Tests of A 35 A Aerobic Power, Tests of. Fig. 3 Example incremental protocols for cycle ergometry (a–c) and treadmill running (d–e). In (a) power output is increased by 30 W every 3 min using either a continuous or discontinuous protocol (note the markedly increased test duration for the discontinuous protocol). In b and c power output is increased using three different increments (10, 20, or 30 W min 1) in a ramp (b) or stepwise (c) fashion. In d the treadmill protocol has a fixed belt speed at 5.3 km h 1 but the gradient increases 1% every minute until exhaustion (Balke protocol). In contrast, in e both the belt speed (2.7–9.7 km h 1) and gradient (0–22%) are increased in a stepwise fashion until exhaustion (Bruce protocol) 36 A Aerobic Power, Tests of (e.g., 10–20 W) followed by an individualized (see below) or predetermined power output increment until exhaustion. This is typically defined as a fall in pedal cadence of 10 rev min 1 below that prescribed (usually between 60 and 80 rev min 1). Alternatively, treadmill protocols typically start at a fixed speed and the exercise intensity is increased by altering the gradient until exhaustion (e.g., Harbor protocol), or until a given gradient is reached and the exercise intensity is further enhanced by increases in treadmill belt speed (e.g., Balke test), or a combination of both (e.g., Bruce protocol). Such tests are more routinely used in the clinical environment or in the general population (see [1, 5] for an overview). For athletic or highly active participants, such tests may end at a very high gradient (>20%) caused by lower limb fatigue and/or discomfort, rather than a cardiorespiratory limitation. Therefore, a protocol that increases in treadmill belt speed initially until the achievement of 80% their heart rate predicted maximum (220 – age), after which the gradient can be increased 1–2% each stage until exhaustion, may be more appropriate. It has been suggested that providing the incremental exercise test is between 8 and 12 min in duration, a valid _ 2 max can be obtained [5]. To achieve this test duration, VO the rate at which the exercise intensity is increased can be _ 2 max tailored to each participant based on their predicted VO _ and VO2 during unloaded cycling [5]: _ 2 during unloaded cycling Predicted VO ¼ 510 þ ð6  weight ½kgŠÞ _ 2 max for males Predicted VO ¼ ðheight½cmŠ age ½yŠÞ  20 _ 2 max for females Predicted VO ¼ ðheight ½cmŠ age ½yŠÞ  14 For example, a 30-year-old male (weight = 75 kg, _ 2 during unloaded height = 178 cm) has a predicted VO _ 2 max of cycling of 600 mL min 1 and a predicted VO 2,960 mL min 1. Assuming an O2 cost of cycling of 10 mL min 1 W 1 and a target test duration of 10 min, a ramp rate of a 23.6 W min 1 is recommended ((2,960 – 600)/100 = 23.6 W). In reality however, a ramp rate of 25 W min 1 would be used resulting in a test duration <10 min. It should be noted that these calculations are “broad brush” estimates and that the experience of the investigator combined with knowledge of the participant’s medical history and physical activity status is likely to result in modifications to the power output increment. The advantage of this cycling protocol, however, is that only the power output increment needs to be manipulated and typically ranges from 10 W min 1 for patients with cardiopulmonary disease and young children, up to 50 W min 1 for elite athletes. Submaximal Exercise Testing _ 2 max or a symptomAlthough direct determination of VO _ limited VO2 peak using an incremental exercise test to exhaustion is considered the “gold standard” approach, such tests are not always feasible due to the requirement for specialized equipment and trained personnel. Therefore, there has been a great interest in developing submaximal protocols, largely based on heart rate responses obtained under steady-state conditions, to esti_ 2 max . While submaximal protocols offer a less mate VO strenuous and technically simplified protocol to estimate _ 2 max , care must be taken when interpreting the outVO come in the context of the error that is associated with the prediction. The reasons for this error are likely to be _ 2 related to the assumed linearity between heart rate, VO and power output during incremental exercise, the error in predicting an age adjusted maximal heart rate (up to 15 beats min 1), the assumption that mechanical efficiency during cycling is relatively fixed across all participants, and the method used to quantify heart rate (e.g., palpation vs. short-range telemetry) [2]. In addition, environmental (e.g., ambient temperature), dietary (e.g., caffeine), and behavioral (e.g., anxiety) factors can all influence the heart rate response to exercise and should be adequately controlled for [1]. Finally, prediction equations should only be used with participants that reflect closely the specific characteristics (e.g., age, sex, and physical activity status) of the original sample. Failure to do so _ 2 max . will introduce further error in the predicted VO Perhaps the most popular submaximal prediction of _ 2 max is the Åstrand-Rhyming nomogram which is VO recommended by the American College of Sports Medicine (ACSM) [1]. The test is relatively straightforward as it requires a steady-state heart rate between 125 and 170 beats min 1 to be obtained during 6 min of cycling at 50 rev min 1 at a single power output. The heart rate at a given power output is then used to estimate the partic_ 2 max using a nomogram following correction ipant’s VO for the age-related decline in maximal heart rate [2]. Alternatively, multiple submaximal power outputs, such as the YMCA cycle test, also recommended by the ACSM, _ 2 max [1]. Using 3 min stages, may be used to predict VO between two and four submaximal heart rates are recorded within the range of 110 beats min 1 and 85% age-predicted maximum and plotted against power output. A linear regression is then used to extrapolate to the Agility power output that corresponds to their age-predicted maximum heart rate. By entering the participant’s predicted maximal power output and body mass into _ 2 max can be estimated [1]: standard formulae, VO _ 2 max ðmL
min 1 Þ VO
¼ 1:8  power output ½kg
m
min 1 Š =body mass ½kgŠ Note: to convert W to kg·m·min 1 use the conversion factor 6.12. While not as popular as submaximal cycling tests, treadmill and stepping protocols are available for estimat_ 2 max [1]. Likewise, indirect predictions of VO _ 2 max ing VO can be obtained using field-based tests, including the 20 m shuttle running test, or time (e.g., 1 mile test) and distance (e.g., 6 min test)-based tests [1]. While requiring a maximal effort, such tests are useful for estimating the aerobic power of large groups of healthy participants in a timeefficient manner. A Aerobic–Anaerobic Threshold (AAT) Is defined as a transition zone in which the metabolism of a working muscle shifts from purely aerobic to partially anaerobic lactacid in a given exercise situation. Cross-References ▶ Anaerobic Threshold ▶ Lactate Threshold Age Usually measured in humans by number of years. References 1. 2. 3. 4. 5. ACSM (2010) ACSM’s guidelines for exercise testing and prescription. Lippincott Williams and Wilkins, Baltimore Astrand P-O, Rodahl K, Dahl HA, Stromme SB (2003) Textbook of work physiology: physiological bases of exercise. Human Kinetics, Champaign Barker AR, Williams CA, Jones AM, Armstrong N (2011) Establishing maximal oxygen uptake in young people during a ramp cycle test to exhaustion. Br J Sports Med 45:498–503 Howley ET, Bassett DR Jr, Welch HG (1995) Criteria for maximal oxygen uptake: review and commentary. Med Sci Sports Exerc 27:1292–1301 Wasserman K, Hansen J, Sue D, Stringer W, Whipp B (2005) Principles of exercise testing and interpretation: including pathophysiology and clinical application. Lippincott Williams & Wilkins, Philadelphia Aerobic Respiration Aged Athlete ▶ Aging Athlete Agility JEREMY M. SHEPPARD1, TIM J. GABBETT2 1 Department of Biomedical, Health, and Exercise Sciences, Edith Cowan University, Joondalup, Australia 2 The University of Queensland, School of Human Movement Studies, Brisbane, Australia Synonyms Change of direction speed ▶ Aerobic Metabolism Definition Aerobic Training ▶ Endurance Training Aerobic Work Capacity _ 2 max ) ▶ Maximal Oxygen Uptake (VO Classically, agility has been defined as the ability to change direction rapidly and accurately. However, this definition and similar definitions fail to recognize that cognitive skills such as anticipation and decision making are generally involved in most movements in the sport setting. The difficulty in finding an accepted definition of agility may be due to the multiple factors from the various sport science disciplines that influence agility performance. Bloomfield et al. [1] suggested that the difficulty in defining agility stems from the multiple individual skills involved in performing a task that is seen as an agile 37 A 38 A Agility movement. A comprehensive definition of agility would recognize the technical skills, cognitive processes, and physical demands involved in agility performance. An agility task may be best described as a rapid, wholebody change of direction or speed in response to a stimulus [5]. As noted by Young et al. [7], agility can be separated into subcomponents that are comprised of both physical qualities as well as cognitive abilities (Fig. 1). These more exclusive descriptions and definitions differ from previous uses of the term agility that have generally been described as solely dependent on physical components such as “rapid change of direction.” In other words, agility is an open skill that requires physical action (change of direction or speed) in response to a domain-specific stimulus. Characteristics In many sports, athletes perform sprints, as well as sprints with rapid deceleration and changes of direction. As such, speed and speed in changing direction is a clear determinant of performance in many sports and therefore should be an emphasis in the preparation of these athletes. However, speed qualities such as acceleration and acceleration with changes of direction are somewhat distinct from each other, and likely require individual attention to maximize performance application to the sporting context [8]. Furthermore, the speed and change of direction qualities of an athlete are underpinned by a multifactorial model of strength qualities, techniques, and other related variables that also need to be addressed [5, 7]. Preplanned changes in direction often occur in the sport setting. However, speed and directional changes in the sporting context are also often performed in response to a stimulus, such as an opposing player’s movements or the movement of a ball (e.g., from an opponent’s racquet). As such, cognitive skills are highly important to agility performance. Perceptual qualities (e.g., reduced decision-making time) have been shown to discriminate between higher and lesser-skilled performers despite similarities in physical abilities (e.g., speed and change of direction speed) [4, 6]. It therefore can be asserted that “agile” athletes require well-developed physical qualities to move and execute skills within the field of play, as well as highly trained domain-specific cognitive abilities to attend to appropriate cues and execute rapid and accurate decisions [2, 4, 6]. Considering the multifactorial nature of agility and its sub-qualities (Fig. 1), it is important for the practitioner to attend to the qualities most relevant to the sport in question, and also to the individual athlete. It has been well established that speed and its specific subqualities (e.g., acceleration, change of direction speed) are highly trainable [8]. Generally, this has been observed by employing a low-volume, that is, training regimen (<500 m, 2–3 sessions/week) of sprint and change of direction speed activities. However, not to be overlooked is the profound impact of speed’s underpinning qualities on overall performance in speed and agility tasks. For example, if an athlete is limited in their strength, and they improve this quality, they will most certainly improve their acceleration and likely their performance in change of direction tasks [7]. Using the model illustrated in Fig. 1, this could in theory lead to improvements in agility by broadly improving the physical components of the athlete. Perceptual (e.g., anticipation) and decision-making skills appear to be trainable through integrating cognitive and physical components into the training regimen. In other words, by incorporating sport-relevant open skill tasks, agility performance can be improved. This is generally accomplished through combined “speed-agility” training sessions where athletes perform not only closed skill Agility Perceptual and decision making Visual scanning Anticipation Pattern recognition Change of direction speed Situational knowledge Foot placement Agility. Fig. 1 Theoretical model of agility components [7] Technique Adjustment of strides to accelerate and decelerate Straight sprinting speed Body lean and posture Leg muscle qualities Strength Power Anthropometry Reactive strength Agility speed and change of direction speed training, but also open skill reactive tasks of a general but sport-relevant nature (e.g., 1 on 1 tagging games) and also of a highly specific nature (e.g., 1 on 1, 2 on 2 offensive–defensive drills). In addition, domain-specific perceptual and decisionmaking skills can be enhanced through video-based occlusion techniques [3]. Video-based occlusion techniques generally involve a sport-relevant sequence on display to the athlete, with this video sequence occluded prior to the execution of the task of interest. For example, a tennis serve might be displayed until 50 ms prior to ball contact, and the athlete is required to either physically respond to the “serve” or describe the serve (i.e., direction and type). After this occurs, the complete and un-occluded sequence can be played in its entirety to reinforce correct perception or incorrect responses. Using a variety of clips, the practitioner can increase the temporal stress of the training over time by occluding the skill earlier in the execution of the task (e.g., 50, 75, 100 ms prior to contact in the serve). This and other implicit learning methods have been successful in several sports. Importantly, the skills developed in this manner appear to offer a robust learning stimulus, with some studies reporting a direct transfer of the competitive environment, and the retention of anticipatory skill even when the training stimulus is removed for a period [3]. A Measurements While the majority of agility testing has been devoted to preplanned change of direction speed tests, researchers have recently begun to investigate the perceptual components of agility, with particular focus on the ability of team sport athletes to “read and react” to a game-specific stimulus in the testing protocol [2, 4, 6]. Sheppard et al. [6] demonstrated that a test of agility, called the Reactive Agility Test, that included the measurement of an athlete’s movement speed in changing direction in response to the change of direction of an “opponent,” was reliable and able to discriminate higher and lesser skilled Australian football players [6], with similar findings observed in rugby league [4], netball [2], and softball [3]. These findings may reflect the fact that effective agility performance is limited by both physical (e.g., linear speed, strength, change of direction speed) and perceptual/decision-making (visual scanning, anticipation, pattern recognition, and situational knowledge) factors. It is suggested that agility be developed and assessed with training and testing that involves both movement speed and decision-making speed and accuracy [4, 5]. The results of these assessments would allow the practitioners to profile and create an individual-needs analysis of their athletes, as suggested by Gabbett et al. [4], and outlined in Table 1. Agility. Table 1 Interpretation and training prescription for four players with different results on the reactive agility test. Gabbett, Kelly, and Sheppard (2008) Player Decision Movement time (ms) time (s) Interpretation Prescription Fast mover–fast thinker 58.75 2.31 Speed and fast decision Continue to develop change of direction time contribute to speed and decision-making skills. above-average anticipation skills. Fast mover–slow thinker 148.75 2.33 Has speed but slow decision time contributes to below-average anticipation skills. Needs more decision-making training on (e.g., reactive agility training) and off (e.g., video-based perceptual training) the field. Slow mover–fast thinker 28.75 2.85 Perceptually skilled, but lacks change of direction speed. Needs more speed/change of direction speed training to improve physical attributes. Slow mover–slow thinker 112.50 2.86 Poor speed and slow decision time contributes to below average anticipation skills. Needs more decision-making and speed/change of direction speed training to improve physical attributes and perceptual skill. Fast movers/fast thinkers = good change of direction speed and good perceptual skill Fast movers/slow thinkers = good change of direction speed and below average perceptual skill Slow movers/fast thinkers = below average change of direction speed and good perceptual skill Slow movers/slow thinkers = below average change of direction speed and below average perceptual skill 39 A 40 A Aging Using the results of the speed and decision-making times in the examples in Table 1, the practitioner can allocate athletes into groups according to their differing training requirements. For example, the “slow mover–fast thinker” would devote a larger percentage of training time to physical components of agility performance, while the “fast mover–slow thinker” would devote a larger percentage of training time to perceptual training and/or training that was “open skill” (i.e., including a high perceptual demand) in nature. For the “fast mover–slow thinker,” a combination of open skill agility tasks and small-sided games could be performed in conjunction with implicit video-based perceptual training and other domainspecific anticipation and decision-making tasks. Finally, for the “slow mover–slow thinker,” training would include an emphasis on sprint-running, change of direction speed, and its underpinning qualities such as technique coaching, strength development, etc., as well as game-specific perceptual (decision-making) training. References 1. 2. 3. 4. 5. 6. 7. 8. Bloomfield J, Ackland TR, Elliot BC (1994) Applied anatomy and biomechanics in sport. Melbourne, Blackwell Scientific, p 374 Farrow D, Young W, Bruce L (2005) The development of a test of reactive agility for netball: a new methodology. J Sci Med Sport 8:52–60 Gabbett T, Rubinoff M, Thorburn L, Farrow D (2007) Testing and training anticipation skills in softball fielders. Int J Sport Sci Coach 2:15–24 Gabbett TJ, Kelly JN, Sheppard JM (2008) Speed, change of direction speed, and reactive agility of rugby league players. J Strength Cond Res 22:174–181 Sheppard JM, Young W (2006) Agility Literature Review: classifications, training and testing. J Sport Sci 24:919–932 Sheppard JM, Young WB, Doyle TLA, Sheppard TA, Newton RU (2006) An evaluation of a new test of reactive agility and its relationship to sprint speed and change of direction speed. J Sci Med Sport 9:342–349 Young WB, James R, Montgomery I (2002) Is muscle power related to running speed with changes of direction? J Sports Med Phys Fit 43:282–288 Young WB, McDowell MH, Scarlett BJ (2001) Specificity of sprint and agility training methods. J Strength Cond Res 15:315–319 Aging The process of growing old associated with deteriorative changes with time that renders organisms vulnerable to challenge and a decreased ability to survive. It covers natural changes in function that occur across the lifespan, which are not caused by disease. Aging can result from a failure of body cells to function normally or to produce sufficient new cells to replace those that have died or malfunctioned. With respect to deteriorative changes, “senescence” is a synonym and describes the state or process of aging. Aging Athlete HIROFUMI TANAKA Department of Kinesiology and Health Education, Cardiovascular Aging Research Laboratory, University of Texas at Austin, Austin, TX, USA Synonyms Aged athlete; Master’s athletes; Old competitor; Senior athlete; Veteran athlete Definition There is no general agreement on the age at which an athlete becomes a masters or aging athlete. This is similar to a lack of definition for an older or elderly person. Although most organizations and agencies have accepted the chronological age of 65 years as a definition of elderly, chronological ages of 50, 55, and 60 years have also been used. In the masters sports, because of a lack of an accepted definition, the age at which an athlete became eligible for the senior or veteran competitions has become the default definition. However, the starting age varies widely among different athletic events; 25 years in masters swimming, 30 years in track and field, 35 years in weightlifting, 40 years in long distance running, and 50 years in senior games. In this entry, the masters athletes are defined as exercise-trained individuals who compete in athletic events at a high level well beyond a typical athletic retirement age. Characteristics It is apparent that the demographics of age in most industrialized countries, including the United States, is changing dramatically. The percentage of older adults will continue to rise for the foreseeable future. This would create potentially unmanageable situations from both economical and societal standpoints since older adults demonstrate the highest rates of morbidity, functional disability, loss of independence, and mortality. A unique group of older adults that are situated at the completely opposite end of the functional capacity spectrum is masters athletes (Fig. 1). In contrast to the high prevalence of Aging Athlete A A Masters Athletes Physical weakness Exhaustion Vascular Disease Metabolic Disease Fall Risks Physical Activity Functional Capacity Physiological Reserve Cognitive Function Wellbeing Frail Elderly Aging Athlete. Fig. 1 Contrasting positions of masters athletes and frail elderly in the functional and disease spectrum sedentary lifestyle and frailty in the overall aging population, the masters athletes comprise an extremely small portions of older adults. These groups of athletes are challenging the prevalent notion that aging is an inevitable process of deterioration that not much can be done to retard or minimize it. Observing young elite runners finishing marathon races in little over 2 h is certainly amazing. But a 73-year-old masters athlete who breaks 3-h mark in marathon is equally marvelous. It is simply amazing or even amusing to observe a 95-year-old sprinter exerting maximal effort to sprint 100 m. This tiny Japanese runner who stood 146 cm and weighed 38 kg (Kozo Haraguchi) ran 22.04 s. Two months later, he broke the record again by running 21.69 s. These exceptional individual athletic achievements are fascinating not only to the aging individuals but also to those of us who study the effects of aging [2]. Aging athletes continue to improve and shutter age-group records in most athletic events ranging from sprint to endurance events. Indeed, yearly improvements in athletic records are substantially greater in older age groups, rapidly closing the gap between younger and older athletes. In these days, masters athlete over the age of 60 can run faster in 100 m sprint than the gold medal winner in the first Olympic games in Athens [1]. In marathon, the time achieved by 75-year-old man is faster than the time of the gold medalist in the first Olympics [1]. In conjunction with the remarkable improvements in athletic performance in older senior athletes, increasing number of elite athletes are remaining in the athletic events way past the typical athletic retirement age and are experiencing success against much younger counterparts. In some cases, 41 they compete against the opponents half of their age. Some particularly noteworthy examples of such success are listed below. ● Dara Torres, Olympic swimming silver medalist at age 41 ● Hilde Pedersen, Olympic cross-country skiing silver medalist at age 41 ● Carlos Lopez, Olympic marathon gold medalist at age 42 ● Randy Couture, UFC mixed martial arts champion at age 44 ● Nolan Ryan, baseball pitcher throwing no hitter at age 44 ● George Foreman, Boxing heavy weight champion at age 45 ● Jack Nicklaus, Masters golf tournament winner at age 46 ● Martina Navratilova, US Open tennis champion at age 49 ● Gordie Howe, all-star NHL ice hockey player at age 52 ● Albert Beckles, body building Mr. Olympia title at age 52 ● Willie Shoemaker, the Kentucky Derby winner at age 54 These exceptional performances may be considered unreachable for most individuals. But it sets the upper limit or a barometer of what is possible for aging adults in general and aging athletes in particular. Masters athletes continue to raise the ceilings of what aging humans can accomplish and break the barriers of physical limitations of older adults. 42 A Aging Athlete Training/Exercise Response Peak athletic performance decreases with advancing age in a curvilinear fashion [2]. In general, peak athletic performance is maintained until a given age (35 years in endurance events) followed by modest decreases with progressively steeper reductions thereafter. A recently published longitudinal study indicates that maximal aerobic capacity may also decline curvilinearly with advancing age. There is no question that declines in the exercise training “stimuli” with advancing age play an important role in reductions in athletic performance and functional capacity [1]. In a study that evaluated 24 senior track athletes between the ages of 50 and 82 years, about half of them quit competing and reduced training and the other half remained very competitive. The senior athletes who remained competitive and continued to train hard maintained their maximal aerobic capacity over a 10-year period whereas those athletes who became noncompetitive demonstrated a large decline in maximal aerobic capacity [3]. Although exercise training volume and intensity can be maintained up to 10 years, there is no evidence that exercise training volume and intensity can be maintained for longer periods, especially in older adults (e.g., 20 years) [3]. Jobs, family responsibilities, injuries, and reduced motivation all appear to contribute to the reductions in training stimuli in older athletes. When the aforementioned senior track athletes were followed up another 10 years later (over a 20-year period), all the runners reduced their training intensity and volume and experienced substantial declines in maximal aerobic capacity [3]. Improvements in training and conditioning techniques, and cares provided by athletic training and sports medicine, appear to have contributed to better preservation of athletic ability and athletic records with advancing age. Indeed, many aging athletes can surround them with an army of athletic trainer, physiologist, nutritionist, biomechanist, and massage therapist. Could masters athletes maintain exercise training and athletic performance in these surroundings? Certainly, this “racing car” approach is becoming a common practice among elite aging athletes. However, exact role and contribution of these supporting staff have not been evaluated, especially in the context of masters athletes. In marked contrast to the prevalent presumptions that masters athletes are life-long trained athletes and that their high athletic performance was acquired from years of accumulated exercise training since they were youth, most of the currently successful masters athletes inherited the exercise training habit and emerged in the competition very late in life. In the case of the aforementioned Japanese sprinter Kozo Haraguchi, he started jogging at 65 years of age for health reasons after the retirement from his job and turned to 100 m sprint when he was 75 years of age. It is of great interest if current world-class athletes were to continue to train and compete as hard, as frequent, and as long as when they were young, what athletic records can be achieved at older age. Recently, Joan Benoit, who won the gold medal at the 1984 Olympic games in Los Angeles, recorded the fastest ever performance by a woman over 52 years of age at the Chicago marathon. Clinical Relevance Human aging is associated with arterial dysfunction and an increased risk of clinical cardiovascular disease. Advancing age is now a major risk factor for cardiovascular disease. In general, a physically active lifestyle is associated with more favorable risk factors and reduced incidence of cardiovascular disease. There is accumulating evidence indicating that masters athletes demonstrate more favorable levels of risk factors for cardiovascular disease than their sedentary counterparts [4]. In many cases, age-related deteriorations of vascular function as well as elevations in vascular risk factors that typically observed in sedentary adults are substantially attenuated or even absent in masters athletes. For example, progressive increases in arterial stiffening with age observed in sedentary adults are markedly attenuated in endurance-trained masters athletes. Additionally, the elevations in systolic blood pressure and pulse pressure seen with age in sedentary adults are absent in those who participate in high-level athletic competition [4]. Furthermore, compared with that observed in sedentary adults, the age-related increases in body weight and in body fatness are smaller or even absent in masters athletes, due in part to the elevated levels of basal metabolic rate. In addition to much lower prevalence of cardiovascular disease, the masters athletes possess greater levels of functional capacity than sedentary adults (Fig. 1). They are also capable of performing physical tasks with much more reserve and much less exertion than their sedentary peers. The “masters athlete model” will continue to be a rich source of insight into our strategy to maintain physiological function and minimize disease risks with advancing age. Achieving and maintaining physical activity levels are one of the most difficult elements of exercise prescription as 50% of adults who initiate exercise programs quit within 6 months. For one, we can attempt to reveal the secret of masters athletes as to how they are motivated to continue exercising vigorously into older ages. These exceptional aging athletes will also be an Aging, Adaptations to Training inspiration for ever growing elderly population who often suffer from chronic degenerative diseases and functional disability. " He’s soft and he’s fat and he’s wearing my clothes and he’s getting too old and he was born on my birthday and I’m afraid if I stop running, he’ll catch up with me. (The Nike poster depicting an aging athlete) References 1. 2. 3. 4. Tanaka H, Seals DR (2008) Endurance exercise performance in masters athletes: age-associated changes and underlying physiological mechanisms. J Physiol 586(Pt 1):55–63 Tanaka H, Seals DR (2003) Dynamic exercise performance in masters athletes: insight into the effects of primary human aging on physiological functional capacity. J Appl Physiol 95(5):2152–2162 Pollock ML, Mengelkoch LJ, Graves JE et al (1997) Twenty-year follow-up of aerobic power and body composition of older track athletes. J Appl Physiol 82(5):1508–1516 Seals DR, Desouza CA, Donato AJ, Tanaka H (2008) Habitual exercise and arterial aging. J Appl Physiol 105(4):1323–1332 Aging, Adaptations to Training M. G. BEMBEN Department of Health and Exercise Science, University of Oklahoma, Norman, OK, USA Definition Aging defies an easy definition, at least in biological terms, since not all organ systems age in the same way or at the same rate or extent in any individual in a given species. However, a few things are certain; aging is developmental or progressive, and aging is a gift of twentieth century technology and scientific advancements. Historically, old age was based on government determined social policies that created social security to begin at 65 years of age; however, it is not uncommon for individuals to reach into their 90s or even 100s since the fastest growing population in the United States are those 85 years and older. Based on these facts, aging can be described as a decreased ability to respond to a changing environment [1]. Adaptation to training implies a semi permanent improvement to a physiological system as the result of attending successive bouts of structured exercise sessions that have been developed based on sound training guidelines that incorporate the following principles: Specificity; Overload, Adaptation, Progression, Retrogression, Maintenance, Individualization; and Warm-up and Cool-down. A Mechanisms The most obvious result that occurs from resistance training is an increase in strength. Increases in muscular strength have been differentiated into different phases of development. Early phase adaptations occurring during the first 2 weeks of training are usually attributed to a learning phase. This phase is often characterized by improved motor skill coordination and an improvement in motivational levels of the participants. The next phase of development that occurs over the next couple of weeks of training usually results in strength increases without a concomitant increase in muscle size and therefore has been attributed to neural adaptations. These neural adaptations can include increased activation of muscle from an increased number of ▶ motor units being activated, an increased firing rate for the motor units, or an improved synchronization of the motor units contracting together. Other factors can also include a better coordination of synergistic and antagonistic muscles, increased neural drive from the central nervous system, decreased electromyographic activity (EMG) in the antagonistic muscles, increased M-wave potentials which might reflect an increase in muscle membrane excitability, selective increases in Type II muscle fiber areas, alterations in muscle architecture, and increases in tendon stiffness. The final phase associated with strength increases following at least 6 week of training are due to muscle hypertrophy [2]. Increases in muscle size or hypertrophy occur as the result of increased rates of protein synthesis. The improved rates of protein synthesis for the elderly following resistance training are similar to that rates exhibited by young people; and have been documented in as short as 2 weeks following the beginning of a resistance training program. This suggests that muscle proteins retain the ability to respond to an overload stimulus and are not limited by advanced age. In addition to the increased rates of protein synthesis, resistance training might also reduce the gene expression and protein levels of Tumor Necrosis Factor alpha (TNFa), a marker of chronic inflammation and an initiator of cell death [3]. In order for hypertrophied muscle to maintain an appropriate ratio between nuclear control and increased mass, it appears that satellite cells are activated during the regenerative phase of skeletal muscle growth [4]. Other factors that have been implicated in satellite cell proliferation and increased muscle cell size are a number of ▶ myogenic regulatory factors that include MyoD, myf-5, myf-6, and myogenin [4]. Ultrasound methodologies have found that increases in strength attributable to muscle hypertrophy can also be explained by an increased length of the muscle fascicles 43 A 44 A Aging, Adaptations to Training and an increased pennation angle, both of which may indicate an increased number of sarcomeres that occur in series to the myofibril, and in parallel to the myofibrils [5]. In other words, there can be an increase in the number of myofibrils within a single muscle fiber, but there are no increases in the number of muscle fibers (hyperplasia) resulting from resistance training adaptations. Increases in muscle power, or the ability to exert force quickly, following training are also reported. Improved muscular power is due to increases in the cross-sectional area of Type II muscle fibers and the increased shortening velocity of these muscle fibers. The increase in power can also be attributable to an earlier activation of motor units and an enhanced motor unit firing rate [2]. Improved muscle endurance can also be the result of muscular adaptation to training. Improved muscle endurance is often evidenced by a decrease in the number of motor units that need to be activated in order to complete a submaximal task, a decreased coactivation of antagonist muscles, increased substrate availability, like adenosine triphosphate (ATP) and phosphocreatine (PC), and increases in mitochondrial density and improved oxidative capacity [6]. Adaptations also occur in the tendons that connect muscle to bone. There is an increase in tensile stiffness due to changes in the material properties of the tendons which might be due to changes in the fibrous structure or the extracellular matrix. This can often cause an increase in the rate of force transmission and a decreased chance of tension injury during exercise. The increase in tendon stiffness may also be associated with the improved development of torque about an axis of rotation which might benefit an older person’s ability to respond to a loss of balance [7]. Exercise Response/Consequences Muscular strength in older adults can significantly increase from 25% to over 100% following properly designed resistance training programs, but increases are often dependent on several complex factors that can include the gender of the subjects training, the duration of the training intervention, the muscle groups being trained, initial fitness levels of those participating in the training program, health status of those training, and the nutritional status of those training. The increase in muscle strength and power following training are often times greater than would be expected if only based on muscle mass changes and are probably indicative of changes in ▶ muscle quality. These strength and power improvements are often associated with a decreased risk of falling, lower risks of hip fractures, and a lower risk for developing osteoporosis in the elderly. The improvements in muscular endurance that can arise as a training adaptation allow older individuals to maintain muscular forces and power over extended periods of time. These adaptations can then improve the ability to carry out normal activities of daily living with less fatigue and help maintain a sufficient energy reserve that might allow an individual to increase their physical activity by engaging in a structured exercise program or to pursue a new recreational activity. Improvements in muscular endurance are facilitated by a number of changes in the vascular network that supplies nutrients and oxygen to the exercising muscle. Adaptations to the cardiovascular system often include improved muscle capillarity as demonstrated by significant increases in the number of capillary contacts per fiber and the capillary to muscle fiber ratio [8]. Diagnostics Assessing Muscle Quantity Estimating Regional Changes to Muscle Mass Anthropometric measures such as limb circumferences corrected for subcutaneous adipose tissue have been used to estimate muscle plus bone cross-sectional areas, although there is substantial error associated with this technique. Muscle plus bone cross-sectional area can be estimated from the following equation: A = (C – ps)2/4p; where A is the estimated muscle plus bone cross-sectional area corrected for subcutaneous adipose tissue, C is the limb circumference, and s is the subcutaneous adipose tissue calculated as the average of half of the skinfold thickness at two opposite locations from the respective limb (anterior and posterior or dorsal and ventral) [9]. Muscle Metabolites Creatinine: Creatinine is formed when creatine is broken down. Creatine is found primarily in skeletal muscle (about 98%) in the form of creatine phosphate. Urinary creatinine excretion is related to the fat-free body mass and skeletal muscle mass, since 1 g of creatinine excreted in a 24 h period is equivalent to about 18–20 kg of muscle tissue, although dependent on factors that include age, gender, and training status and reflects whole body measures of muscle [9]. 3-Methylhistidine: 3-Methylhistidine is an amino acid that is located mostly in skeletal muscle, and the urinary excretion of 3-methylhistidine has been used to estimate whole body muscle mass. Problems with this assessment arise because of different protein consumptions of Aging, Adaptations to Training individuals and the fact that it can also reflect nonskeletal muscle protein turnover (i.e., smooth muscle and connective tissue) [3, 9]. Ultrasound Muscle thickness can be assessed by B-mode ultrasound with an electronic linear array probe (usually 5.0 MHz wave frequency). The frequencies used in diagnostic ultrasound usually range between 2 and 18 MHz. The choice of frequency results in a compromise between spatial resolution of the image and the imaging depth, with lower frequencies producing less resolution but an increased ability to image deeper into the tissues [7]. Radiographic Methods Computed Tomography (CT): Computed tomography is based on the attenuation of x-ray intensities relative to water and is dependent on tissue density. Problems with this technique are a lack of accessibility to very expensive equipment, unnecessary exposure to fairly high doses of ionizing radiation due to the high energy photons associated with x-rays, the high cost of the analyses, and the large variation in the attenuation of different muscle groups [7, 10]. Nuclear Magnetic Resonance (NMR): Nuclear magnetic resonance can provide images of tissue known as MRI (Magnetic Resonance Imaging) or information about the chemical composition of the tissue (NMR Spectroscopy). This technique is based on the concept that the nuclei of atoms act like magnets and when an external magnetic field is applied to the tissue, it absorbs the energy and then emits a radio signal that can be used to develop an image of the chemical composition of the tissues. It can detect the abundance of 31P containing components like ATP, inorganic phosphate, and PC. Many of the problems with this technique are similar to the CT scanning – a lack of accessibility to very expensive equipment, cost of the analyses, etc. [9, 10]. Dual Energy X-Ray Absorptiometry (DXA): Dual energy X-ray absorptiometry is also based on the attenuation of two different energy sources of X-rays which can be used to assess fat and bone-free lean tissue (lean tissue mass). This equipment is also very expensive, but much less than CT and MRI equipment; there is greater accessibility to this type of equipment, and it is much safer than CTscans since it has lower doses of radiation exposure [9]. Peripheral Quantitative Computed Tomography (pQCT): pQCT is restricted to peripheral measurements of the arms and legs but uses very low radiation doses compared to whole body CT scanning. pQCT was originally designed to evaluate both trabecular and cortical A bone mineral densities as a volumetric density (gm/cm3) but has also been used to estimate muscle volumes or muscle cross-sectional areas. Different scan analyses are used to estimate muscle cross-sectional area and involve different thresholds and modes (i.e., contour detection mode or peel mode). Generally, coefficients of variation for muscle cross-sectional areas with this technique are about 1.5%. Muscle Biopsy There are basically two types of muscle biopsies needle biopsies and open biopsies. A needle biopsy involves inserting a needle into the muscle with no previous incision being made. When the needle is removed, a small piece of tissue remains in the needle. An open biopsy involves making a small cut in the skin and into the muscle. The muscle tissue is then removed with a Bergström needle facilitated with suction. Samples are then usually frozen in isopentane, cooled to 160 C before being sectioned and analyzed. Fractional Protein Synthesis Rates of Skeletal Muscle The fractional protein synthesis rates of skeletal muscle can be determined by the incorporation of an intravenously administered stable isotope-labeled amino acid (13C-leucine) into skeletal muscle protein. Gas chromatography-mass spectroscopy then measures muscle cytosolic 13C-leucine, plasma 13C-leucine, and plasma a13C- ketoisoceproil acid enrichment, and gas chromatography-combustion-isotope ratio mass spectroscopy is then used to measure 13C-leucine enrichment in mixed, MCH, and actin proteins [3]. Assessing Muscle Quality Muscle Strength Muscular strength, or the maximal voluntary force generating capabilities of a muscle or muscle group, can be assessed by three different modalities: isometrically, dynamically, and isokinetically. Isometric Strength: Maximal voluntary isometric strength is usually assessed with load cells or force transducers that allow a muscle or muscle group to exert force while no external movement of the limb or limb joint takes place. Typically, values for maximal forces from this technique are greater than those obtained with dynamic assessments or isokinetic assessments since the nature of the tension development during an isometric contraction maximizes the ability for greater motor unit synchronization to take place since no limb movement is occurring. 45 A 46 A Aging, Motor Performance Dynamic Strength: Dynamic strength is the maximal load that can be lifted or moved. This type of assessment usually involves free weights or plate loaded machines, and the standard terminology for this assessment is referred to as 1-RM, or one-repetition maximum. The term 1-RM implies the greatest amount of weight that can be lifted successfully with proper form. Isokinetic Strength: Isokinetic strength or maximal torque is the maximal force about an axis of rotation that can be exerted against a pre-set rate-limiting device. This type of assessment requires specially designed equipment that can control the velocity of the contraction while maximal effort is being generated into a force dynamometer. In other words, no matter how much effort is exerted, the movement takes place at a pre-set constant speed that can range from 0 /s (isometric) to 450 /s. This type of assessment is often used to test and improve muscular strength during rehabilitation from an injury. 3. Yarasheski KE (2003) Exercise, aging and muscle protein metabolism. J Gerontol A Biol Sci Med Sci 58A:918–922 4. Hunter GR, McCarthy JP, Bamman MM (2004) Effects of resistance training on older adults. Sports Med 34:329–348 5. Folland JP, Williams AG (2007) The adaptations to strength training. Morphological and neurological contributions to increased strength. Sports Med 37:145–168 6. Chodzko-Zajko WJ et al (2009) Exercise and physical activity for older adults. Position stand for the American College of Sports Medicine. Med Sci Sports Exerc 41(7):1510–1530 7. Narici MV, Maganaris CN, Reeves ND (2005) Myotendinous alterations and effects of resistance loading in old age. Scand J Med Sci Sports 15:392–401 8. Harris BA (2005) The influence of endurance and resistance exercise on muscle capillarization in the elderly: a review. Acta Physiol Scand 185:89–97 9. Lukaski HC (1996) Estimation of muscle mass. In: Roche AF, Heymsfield SB, Lohman TG (eds) Human body composition. Human Kinetics, Champaign, IL, pp 109–128 10. Lang T, Streeper T, Cawthon P, Baldwin K, Taaffe DR, Harris TB (2010) Sarcopenia: etiology, clinical consequences, intervention. Osteoporos Int 21:543–559 Muscle Power The term power implies the application of a force as quickly as possible. It can be calculated as force multiplied by the velocity of the movement or the force applied over a given distance divided by time taken to complete the task. Some laboratory methods used to assess muscular power include the vertical jump (Lewis Power Jump) or a timed stair run (Margaria-Kalamean Power Stair Run) and is expressed as kg∙m∙s–1, kg∙m∙min–1, or watts. Muscle Endurance Muscle endurance is often described as the ability of a muscle or muscle group to maintain a force or to do repeated submaximal contractions over a given period of time. Muscular endurance can be thought of as the opposite of muscular fatigue, in other words, the greater the endurance capacity of muscle the less fatigue that is exhibited in terms of a declining force output. Most activities of daily living require good muscle endurance and seldom require maximal effort or maximal strength. These types of activities can include shopping, carry groceries, and gardening, for example. Muscular endurance can be assessed by evaluating the number of submaximal repetitions that can be completed before total or partial fatigue occurs. References 1. Smith EL (1981) Age: the interaction of nature and nurture. In: Smith EL, Serfass RC (eds) Exercise and aging: the scientific basis. Enslow Publishers, New Jersey, pp 11–17 2. Macaluso A, De Vito G (2004) Muscle strength, power, and adapatations to resistance training in older people. Eur J Appl Physiol 91:450–472 Aging, Motor Performance SCOTT K. LYNN1, GUILLERMO J. NOFFAL1, DAVID M. LINDSAY2, ANTHONY A. VANDERVOORT3 1 Department of Kinesiology, California State University, Fullerton, CA, USA 2 University of Calgary, Calgary, AB, Canada 3 School of Physical Therapy, University of Western Ontario, Ontario, Canada Synonyms Gerontology; Master’s athletes; Movement control in older people; Neuromuscular aging Definition It is well known from the results of masters competitions throughout the world that motor performance of the athletes declines with ▶ age. Furthermore this gerontological effect can also be observed longitudinally by following the changes in scores, speed or distance achieved of elite sportspersons who continue their participation over several decades, sometimes into very old age [1]. Thus to ensure a fair competition, events are organized into various age groupings across the adult ▶ lifespan, and these categories depend upon each sport’s requirements. Most tissues and systems of the body experience an age-related loss of physiological capacity to some degree, although it can be debated whether such effects are maladaptive under all Aging, Motor Performance circumstances. For example, there is conclusive evidence that the typical mixture of fast and slow myosin fibers that comprises human muscles shifts in favor of the latter type in old age, which reduces speed of response but enhances aerobic metabolism. In this entry, we will first discuss the general mechanisms of ▶ aging within the motor performance system, and then utilize the sport of golf to illustrate how such age-related changes affect the exercise response. Mechanisms Functions of the neuromuscular, sensory, skeletal, and cardiorespiratory systems are each integral to performance of physical activity, and all affected significantly by the aging process [2–4]. The age-related trends for nerve, muscle, and bone tissues that directly affect motor performance are summarized for the reader in the Table. Muscle strength is one of the more obvious examples of how physical parameters are influenced by age. Absolute strength increases through the growth years of childhood and adolescence up to one’s early 20s, has a general plateau phase until the fifth decade, and then decreases by about 10% per decade thereafter [4, 5]. The decline in strength is primarily the result of decreased muscle mass (age-related ▶ sarcopenia), due to the loss of functioning ▶ motor units consisting of motor neurons and the family of fibers they innervate. Total muscle cross sectional area declines by 10% between the ages 24 and 50, then drops another 30% between ages 50 and 80 years and beyond. Equal amounts of both type 1 (slow twitch) and type 2 (fast twitch) muscle fibers are lost with old age. However, in addition to overall fiber loss, type 2 fibers also undergo a much greater decrease in size compared to their type 1 counterparts, and thus the older athlete has an even further reduced capacity for generating muscle power. The resultant pattern of the sarcopenic strength loss is such that a middle-aged golfer would not be expected to have any significant decrease in maximum isometric or concentric strength compared to a young player, but an 80-year-old would have only about half the overall strength level of the young adult. It is quite interesting to note that golf performance tends to follow the same pattern, as evidenced by comparisons of average ▶ golf “handicaps” versus age – handicap being a sport-specific, standardized way of monitoring a golfer’s scores, and hence ability. Recreational golfers tend to reach their prime in the third decade and then begin to experience some loss of performance after their forties. However, they can still continue to play well and even compete with other age groups via the handicap system for the rest of their lives. For example, adolescents who are learning the game are expected to have higher scores than young adults at the A peak of their performance years, but then players in older age groups would also have more of a benefit on average from the handicap index factor. Thus the older golfer’s “net” score can be adjusted statistically to compare expected performance on a more equal basis. Exercise Response It is important to note that the aging muscular system remains quite adaptable to exercise programming [2, 3, 5] and so there are definite benefits for senior golfers who decide to take up a ▶ resistance training program that trains the appropriate patterns of movement that can help to optimize the ability to generate effective muscle forces for the golf swing. These types of programs can also be valuable for the prevention of musculoskeletal injuries and degenerative joint changes. Furthermore, our recent research has shown that older individuals can take advantage of the muscle strengthening benefits of eccentric overload resistance training principles, and that this mode of exercise also causes less cardiovascular stress compared to concentric exercises [4]. Finally, it is useful to take advantage of any motor learning associated with the training exercises, especially those involving coordinated ballistic movements among several muscles. Therefore, it would seem logical to design some of the exercises to simulate the golf swing with its various concentric and eccentric activation muscle patterns, thereby stimulating adaptation within the appropriate musculature and neural pathways. Another common complaint of older golfers is generalized stiffness in several of the key joints involved in the golf swing. From a physiological standpoint, much of this stiffness relates to connective tissue changes within the body, due to the significant water loss with age that contributes to a reduction in this tissue’s plasticity. There may also be osteoarthritic changes in the joints that affect the older golfer’s ability to assume the desirable athletic posture and movements for a full, powerful swing [6]. Clinically, age-related changes in connective tissue are manifested by losses in flexibility from key joints of the body that generate power for the swing such as the trunk and shoulders. As an example study, Thompson and Osness [7] examined muscle strength and flexibility in older male recreational golfers (mean age = 65.1 years), and determined that both ▶ resistance training and flexibility exercises emphasizing trunk rotation were related to improvements in clubhead speed and flexibility for golf. Even though this gain in rotational flexibility increases clubhead speed, one must be careful to avoid excessive spinal motion because it can actually be a risk factor for future back troubles. This risk is thought to arise from 47 A 48 A Aging, Motor Performance twisting of the annulus fibrosis, which combined with spinal flexion greatly increases the chances of posterior disk herniation [8]. To summarize, all golfers continually hope to improve their game, however the older golfer is also dealing with age-related changes and may be content with simply not having their performance decline. For example, typical club head speed decreases as the golfer ages but there are encouraging examples from studies of exercise programs after which increases in clubhead speed are likely a result of the cumulative impact of increasing flexibility of key muscles, along with the benefits of increasing overall muscle strength. Even simply following a maintenance program as one ages is a good strategy for some if it Aging, Motor Performance. Table 1 Effects of training and warm-up on age-related changes in aspects of motor function System Changes with aging Effects of warm-up Effects of activity Muscle – Max strength 25–50 years, then decline of 1.5%/year after 60 – ↓ Number of motor units – ↓ Number of muscle fibers – ↓ The size of Type II fibers – Some lean muscle replaced with fat and connective tissue – General body warm-up increases blood flow and body temperature, which speeds up muscle contraction – Static and Dynamic stretching alter the biomechanical length-tension relationship of shortened “tight muscles – Plays a key role in maintenance of muscle mass – Overload training ↑ muscular strength – Changes in cross sectional area ↑ with training – Early strength gains primarily by neurological adaptation then some hypertrophy possible Nervous system – Muscle atrophy contributed to by neurological changes – 37% ↓ Number of spinal cord axons – 10% ↓ Nerve conduction velocity in older adults – ↓ Sensory and proprioception function – ↓ Reflex speed when responding to stimuli – General body warm-up increases blood flow to the brain, which enhances alertness and cognitive function (“getting into the zone”) – Dynamic stretching and specific motor rehearsal enhance coordination of muscle activation sequences, plus postural control – Activity allows rapid response time to remain relatively unchanged in older adults – Balance can be improved with specific strengthening exercises and postural maneuvers Skeletal – After third and fourth decade ↓ mineralization of 0.3–0.5%/year – Over lifetime: 35% of cortical and 50% of trabecular bone is lost – Men only lose 2/3 the bone mass which females lose, i.e., notable menopause effect – General body warm-up, plus and Static and Dynamic Stretching gradually increase range of motion for stiffened joints (e.g., shoulders and wrists) to maximum levels needed for full swing – Gravitational loading and muscular traction found to affect: bone thickness, strength, calcium concentration – Regular activity found to help counteract demineralization Connective tissue – Altered proportions and properties of connective components – ↑ Stability of cross-links in collagen, ↑ strength, become non-adaptive – ↓ Water and ↓ plasticity – Becomes non-pliable, brittle, weak – Predisposition to tendon and ligament injury – General body warm-up increases blood flow and body temperature, facilitates elongation of connective tissue – Static and dynamic stretching increases flexibility of muscle-tendon units, allowing golfer to obtain desired biomechanical positions for swing – Physical activity known to increase turnover rate of collagen – ↑ Pliability and ↓ formation nonadaptive connective tissue Cartilage – Atrophies with age – Proteoglycan subunits smaller – ↓ Cartilage water content – ↓ Lubrication of joint – Vulnerability to injury – Weight bearing activity throughout the warm-up facilitates diffusion of lubricating fluid into joint space (but need to avoid excessive stresses) – Consistent weight bearing activity over time thickens cartilage and facilitates processes for diffusion of fluid into joint space Note: ↑ increase in variable, ↓ decrease. Gerontological information in Table is based on research summarized in ACSM et al. [2]; Paterson et al. [3]; Vandervoort [4]; Versteegh et al. [9]. Aging, Motor Performance comes from a well-rounded resistance exercise program that trains the appropriate patterns of movement at the correct target level for the individual. Specific focus on certain directions of movement can also be recommended if abnormal patterns of motion are observed. In terms of age-related changes to cardiovascular performance, cardiac output decreases by about 30% between the ages of 30 and 70 years [2, 3]. In golfers, this decrease in aerobic ▶ endurance may cause premature mental and physical fatigue leading to performance inconsistencies, particularly toward the end of a round. As noted above, there can be a significant demand placed on the cardiorespiratory and metabolic systems by the prolonged duration of a typical round of walking the golf course. The effect of limited cardiovascular capacity on performance may further be compounded by localized muscle ▶ fatigue that can occur during ambulation on uneven terrain. Given that the overall ability of older adults to carry an absolute load over time is reduced compared to younger adults, a common mechanism of many sports injuries – fatigue and associated neuromuscular incoordination – is a likely contributing factor. However, fatigue resistance can be also built up with appropriate exercise strategies. While golf performance may be compromised by the diminished cardiovascular capacity of senior players, it should also be mentioned that the muscular and cardiovascular requirements of golf can also provide considerable health benefits. These gains can include increased aerobic performance, as well as improved body composition and high-density lipoprotein serum cholesterol levels. Thus, walking the golf course provides a sufficient amount of physical activity that has been shown to aid overall health and well-being, especially for older golfers whose physiological training threshold is lowered by age [9]. Remarkably, the benefits of a ▶ warm-up session before competition for the older athlete can have many of the same effects as training, albeit to a lesser extent [4, 10]. These effects are also summarized in Table 1. For example, the slowed speed of muscle contraction and power generation in older adults can be altered just by increasing body temperature via the initial lowintensity exercise phase of a typical warm-up routine. Then additional benefits can be derived from ensuring that the connective tissue in muscles and tendons is ready to support the required range of motion of full golf swings. Finally, there is the facilitation of motor coordination that results from rehearsal of the specific swings that will soon be used on the course. From the perspective of injury prevention, it is also valuable to practice the desired movements and incorporate any necessary adjustments to accommodate painful or stiff joints [6]. A Conclusion In summary, there are extensive age-related changes in physical functions that affect the motor performance of older athletes. However, there are also worthwhile advantages of a maintained training program and appropriate warm-up routine for this age group as they prepare to engage in skilled movement patterns for their sport. The example of golf was used due to its high popularity and recognized health benefits for seniors from among the physical activity choices that they have. Due to the agerelated changes in the motor and skeletal systems that reduce the effectiveness of golf swings with optimal tempo and rhythm, training can be essential for performance. Yet most male and female recreational golfers aged 50 or older fail to stay in good physical condition. Senior athletes should be encouraged to participate in continuing training programs throughout the year that include cardiovascular endurance (i.e., if additional physiological stimulation is necessary beyond the effects of walking the course). Overall reductions in the body’s ability to maintain cardiovascular and muscular homeostasis also indicate that older players need to pay close attention to maintaining adequate hydration, nutritional supplementation, and blood electrolytes during their round of golf, particularly in hotter climates. References 1. Spirduso WW, Francis KL, MacRae PG (2005) Physical dimensions of aging, 2nd edn. Human Kinetics, Champaign, Il 2. ACSM, Chodzko-Zajko WJ, Proctor DN et al (2009) American college of sports medicine position stand. Exercise and physical activity for older adults. Med Sci Sports Exerc 41:1510–1530 3. Paterson DH, Jones GR, Rice CL (2007) Ageing and physical activity: evidence to develop exercise recommendations for older adults. Appl Physiol Nutr Metab 32:S69–S108 4. Vandervoort AA (2009) Potential benefits of warm-up for neuromuscular performance of older athletes. Exerc Sports Sci Rev 37:60–65 5. Aagaard P, Suetta C, Caserotti P, Magnusson SP, Kjaer M (2010) Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure. Scand J Med Sci Sports 20:49–64 6. Lynn SK, Noffal GJ (2010) Frontal plane knee moments in golf: effect of target side foot position at address. J Sports Sci Med 9:275–281 7. Thompson CJ, Osness WH (2004) Effects of an 8-week multimodal exercise program on strength, flexibility, and golf performance in 55- to 79-year-old men. J Aging Phys Act 12:144–56 8. Marshall LW, McGill SM (2010) The role of axial torque in disc herniation. Clin Biomech 25:6–9 9. Versteegh TH, Vandervoort AA, Lindsay DM, Lynn SK (2008) Fitness, performance and injury prevention strategies for the senior golfer. Ann Rev Golf Coach 2:199–214 10. Fradkin AJ, Sherman CA, Finch CF (2004) Improving golf performance with a warm up conditioning programme. Brit J Sports Med 38:762–765 49 A 50 A AI (Adequate Intake) AI (Adequate Intake) Term developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies (USA). The AI is defined as the average daily recommended intake level based on observed or experimentally determined estimates of nutrient intake that is assumed to be adequate to sustain health. This term is used when an RDA (recommended daily allowance – the average daily nutrient intake level sufficient to meet the nutrient requirements of 97–98% of healthy individuals) cannot be determined from currently available data. AICAR 5-Aminoimidazole-4-carboxamide-1-b-d-ribofuranoside (AICAR) is an adenosine analog that is taken up by cells and phosphorylated to become 5-Aminoimidazole-4carboxamide-1-b-d-ribofuranosyl 50 -monophosphate (ZMP), an analog of adenosine 50 -monophosphate (AMP). AICAR is commonly used as a means to activate the AMP-activated protein kinase. Cross-References ▶ AMP-Activated Protein Kinase AIDS, Exercise GREGORY A. HAND, G. WILLIAM LYERLY Arnold School of Public Health, Department of Exercise Science, University of South Carolina, Columbia, SC, USA Synonyms Clinical population; HIV; Infection; Physical activity; Resistance training Definition AIDS, acquired immunodeficiency syndrome, is an advanced stage of human immunodeficiency virus (HIV) infection characterized by a CD4 T-cell count below 200 cells/ml of blood and a chronic susceptibility for opportunistic infections. HIV is a retrovirus that targets immune cells that display CD4 surface proteins for infection, then replicates within the cell and kills it. The severe reduction in CD4 lymphocytes, the immune cells most affected by HIV infection, resulting from this infection and replication process is the primary mechanism for HIV-associated immunosuppression [1]. Pathogenetic Mechanisms Infection by HIV, a retrovirus of the lentivirus group, is mediated by physical binding to the CD4 cell surface protein followed by penetration of the cell. Cells that display CD4 molecules, all of which are targets for HIV infection, include T lymphocytes, macrophages, peripheral blood cells various epithelial cells, peripheral nerve cells, testicular Sertoli cells, and hepatic cells. Immunosuppression, resulting from depletion of CD4 T cells, is the hallmark of HIV infection. T cells play a critical role in regulating the systemic immune response, and loss of this function results in development of opportunistic infections in various organs and tissues. As highly active antiretroviral therapy (HAART) has increased the life expectancy of individuals infected with HIV, previously unreported conditions have become a critical concern for maintaining functionality in the individual. These newly identified conditions are chronic with accumulating effects, are typically associated with aging in non-infected populations, and include various physiological and psychological diseases including cardiovascular diseases, muscle wasting and deconditioning syndromes, metabolic disorders, and increased levels of depression, anxiety, and stress. Fatigue, which is a major contributor to physical inactivity, is a commonly reported symptom in those infected with HIV. As a result, HIV-infected individuals usually have lower levels of physical activity, which leads to a reduction in functional capacity and health-related quality of life. This sedentary lifestyle can exacerbate HIV-related symptoms and accelerate the progression of the disease. Exercise Intervention/Therapeutical Consequences Emerging evidence demonstrates that health benefits can be obtained in chronically ill populations through implementation of a structured, moderate-intensity exercise regimen. Similar to what has been seen in other clinical populations, the benefits of aerobic and resistance exercise participation are documented in studies of HIV-infected individuals. Exercise is a potential treatment for many of the symptoms associated with the HIV disease and can elicit improvements in body composition, strength, cardiorespiratory fitness, and mood and well-being [2]. Exercise has been shown to be safe in the HIV-infected population with no reports of adverse side effects. Studies involving regimens comprised of low- to moderateintensity aerobic exercise have shown no increase in AIDS, Exercise prevalence of opportunistic infections, no increase in viral load, and no reduction in CD4+ T-cell count. Some studies have reported enhanced immune function via exercise, especially in asymptomatic individuals. However, these results are controversial. Numerous studies have demonstrated an immunosuppressive effect of large doses of high-intensity exercise training in healthy individuals. Therefore, overtraining should be avoided when prescribing exercise regimens to HIV-infected individuals who are at risk for opportunistic infections. The majority of studies investigating the effects of exercise in the HIV-infected population have focused on aerobic training. The interventions used in these studies have differed greatly in dosage (intensitytime). Studies have varied in duration from 5 weeks to 6 months and intensity levels from low to high. For this reason, dose response interpretations are controversial. However, the preponderance of evidence indicates that HIV-infected individuals can obtain beneficial results in as little as 6 weeks of aerobic activity of at least 2–3 sessions per week. Important adaptations can be categorized as functional, anthropomorphic, biochemical, and psychological. Numerous studies using various doses of exercise have demonstrated significant gains in functional aerobic capacity (FAC) at both high- and moderate-intensity levels, with greater gains being experienced when working at a higher intensity. Additionally, increases in high density lipoprotein (HDL) cholesterol, as well as significant decreases in total abdominal adipose tissue, total cholesterol, and triglycerides (TG) have been shown. One emerging area of beneficial results includes reductions in anxiety and depression. These psychological gains are particularly important since HIV-infected individuals often suffer from social isolation and depression after learning of their HIV infection. Besides these significant changes with aerobic exercise, some studies have observed beneficial changes in immunological variables, including increases in plasma CD4 T-cell counts. However, numerous studies have failed to replicate these findings. Further, it can be proposed that these changes in blood levels of immune cells are an enhanced mobilization of cells into the blood from lymphoid tissues rather than increased overall quantity of cells. Only a few studies have examined the effects of resistance training, independent of aerobic exercise, on the health and fitness of HIV-infected individuals. The majority of these investigations has focused primarily on levels of strength and muscle mass rather than overall fitness or immune function. Further, most have incorporated high-intensity programs. Studies of resistance training report beneficial changes in body composition, including A increases in lean tissue mass (LTM) and overall body mass, increases in muscular strength, decreases in TG, and increases in physical functioning. Lean tissue mass increases have been shown to be positively correlated with the slowing of HIV progression and a decrease in HIV-related mortality. Because of these beneficial effects, resistance training has been prescribed to HIV-infected individuals with varying results. Results suggest that high-intensity resistance training may elicit favorable outcomes, while research is needed to elucidate the effects associated with low- to moderate-intensity resistance training. A growing number of studies are investigating the effects of combined aerobic and resistance exercise training programs that follow the guidelines established by numerous federal agencies and foundations. These combined programs offer several advantages, including enhanced cardiorespiratory function in a population that is typically deconditioned with the additional benefit of strength and muscle mass gains that accompany resistance training. Moderate-intensity combined exercise regimens have been shown to improve total cholesterol, body composition, and psychological well-being as well as increase overall health, and quality of life. Results also demonstrate increases in FAC similar to exercise regimens consisting of only aerobic training, and increases in strength greater than that produced by the aerobic regimens. Thus, combined exercise training likely results in both cardiovascular and musculoskeletal adaptations, making this intervention more appealing than either individual exercise modality. However, the majority of these studies utilized high-intensity resistance training, which often results in poor exercise adherence due to muscle soreness and increased risk of injury in untrained individuals recruited from healthy or clinical populations. As with either mode individually, the optimal dosage of combined training has not been elucidated. Recent work has begun to address the issue of finding a manageable exercise regimen that will enhance program adherence and optimize health benefits. One study has examined the effects of a 6-week combined program in which the physical activity was performed at a moderateintensity level [3]. Results showed a significant training effect that included enhanced FAC, decreased heart rate at absolute submaximal workloads (training bradycardia), increases in LTM, and peak strength increases between 14% and 28% on eight resistance exercises. Circulating levels of cytokines and hormones were also investigated, which resulted in increases in growth hormone (GH), interleukin-6 (IL-6), and decreases in cortisol and soluble tumor necrosis factor receptor-2 (sTNFrII). These changes 51 A 52 A Airway Inflammation in cytokines and hormones are important as they present potential mechanisms for the increases in LTM resulting from the program. Additionally, HIV-infected individuals adhered well to the low-volume, moderate-intensity training. These findings, as well as those from a number of other studies, indicate that HIV-infected individuals can experience beneficial cardiovascular adaptations from short-duration training combining low-volume aerobic and resistance movements at moderate intensity. Importantly, the results also suggest that the functional limitations common in HIV-infected individuals are due in part to detraining and are reversible through moderate exercise adherence [4]. In summary, the preponderance of data indicate that moderate- and higher-intensity aerobic, resistance, and combined exercise regimens can both be safe and elicit beneficial changes in HIV-infected individuals. Benefits observed in controlled trials include changes in body composition, FAC, muscular strength, total and HDL cholesterol, cognitive function, depression and anxiety, self-reported overall health, and quality of life. Conversely, beneficial effects of exercise training on HIV status, viral load, or immune function are controversial. However, aerobic exercise has been shown to have no negative impact on immunity or disease progression. Further research is required in order to determine the minimal and optimal duration, frequency, and intensity of exercise needed to produce beneficial changes in this population. A confounding factor in the majority of studies has been the lifestyle choices of the participants, which include severe deconditioning that is often confused with HIVassociated wasting or other symptoms evoked by poor diet and exercise participation. Further, most studies have yet to approach the exercise program from the perspective of validating commonly used exercise prescriptions, or from a dose response perspective. Both approaches are critical for a full understanding of the effects of training on the HIV-infected population. References 1. 2. 3. 4. http://www.cdc.gov/hiv/ Dudgeon WD, Phillips KD, Carson JA, Brewer RB, Durstine JL, Hand GA (2006) Counteracting muscle wasting in HIV-infected individuals. HIV Med 7:299–310 Hand GA, Phillips KD, Dudgeon WD, Lyerly GW, Durstine JL, Burgess SE (2008) Moderate intensity exercise training reverses functional aerobic impairment in HIV-infected individuals. AIDS Care 20(9):1066–1074 Schmitz HR, Layne JE, Humphrey R (2002) Exercise and HIV infection. In: Myers JN, Herbert WG, Humphrey R (eds) ACSM’s resources for clinical exercise physiology: musculoskeletal, neuromuscular, neoplastic, immunologic, and hematologic conditions. Lippincott Williams & Wilkins, Philadelphia, pp 206–218 Airway Inflammation ▶ Pulmonary System, Training Adaptation Algesic Substances Substances that excite free nerve endings or pain receptors finally eliciting the perception of pain. Alkaline Earth Metal ▶ Magnesium Alkaloid Alkaloids are nitrogenous organic compounds produced by bacteria, fungi, plants, and animals. Many alkaloids are used for therapeutic purposes (e.g., atropine, morphine, caffeine). Allele One possible sequence of DNA at a specific location on a specific chromosome. An allele may refer to a single base in the DNA sequence or a sequence of many bases. Allergy An altered, hypersensitive reaction to second contact with an antigen that causes an allergic reaction that may be local or systemic. Most allergies are characterized by type 1 hypersensitivity. Initial presentation of the antigen results in the production of large number of IgE secreting plasma cells that release antibodies to mast cells, and these release histamine on subsequent presentation of the antigen, leading to an allergic response. Allosteric A molecule allosterically regulates enzyme activity by binding to a non-catalytic site of an enzyme, resulting in either enhancement or inhibition of the catalytic rate. Altitude Sensitivity Allosteric Hemoglobin Modifiers Are substances which increase the deliverance of oxygen by hemoglobin. All-Out Exercise Maximal-intensity exercise, longer in duration that a sprint (i.e., >10 s), where there is a considerable decrease in performance. Alpha1-Adrenergic Receptors One of the three major subfamilies of adrenergic receptor, divided into alpha1A-, alpha1B-, and alpha1Dadrenoceptors. Cross-References ▶ Adrenergic Receptors A Alteration in Structure and Function ▶ Training, Adaptations Altered Modulation of Vasomotor Tone ▶ Endothelial Dysfunction Alternative Activation Alternative activation is a macrophage inflammatory state characterized by the secretion of effectors such as TGFbeta and a series of chemokines (CCL13, CCL23. . .) and growth factors (IGF-1. . .). They express higher levels of scavenger receptors. Alternative activation can be triggered in vitro by IL-4. Alternatively activated macrophages are associated with chronic inflammation. Alpha2-Adrenergic Receptors One of the three major subfamilies of adrenergic receptor, divided into alpha2A-, alpha2B-, and alpha2Cadrenoceptors. Altitude Refers to the height above sea level and in this setting high altitude is defined as 2,500 m and above. Cross-References ▶ Adrenergic Receptors Altitude Illness Alpha-Amylase or Amylase A digestive enzyme found in saliva that begins the digestion of starches in the mouth (also called ptyalin). It also has an antibacterial action. ALS Amyotrophic lateral sclerosis is caused by the degeneration of motor neurons in the spinal cord and brain, resulting in progressive muscle atrophy, paralysis and death. ▶ Acute Mountain Sickness Altitude Sensitivity Altitude sensitivity is defined as the percent difference of maximal oxygen consumption (%DVO2max) when measured at sea level and at a defined altitude. The %DVO2max usually becomes more negative the higher the altitude. %DVO2max is individually different and depends on gender, training state, body fat content, as well as on muscular characteristics. 53 A 54 A Altitude Sickness Altitude Sickness ▶ Acute Mountain Sickness Altitude Training Altitude training is a popular training approach among athletes to increase exercise performance at sea level or to acclimatize to competition at altitude. Muscle structural, biochemical, and molecular findings point to a specific role of the altitude-associated hypoxia in combination with training. It has been reasoned that exercising in hypoxia increases the training stimulus. However the effects of training in hypoxia on aerobic and anaerobic performance as well as strength development are controversial. Hypoxia training studies published in the past have varied considerably in altitude (2,200–5,700 m) and training duration (1–8 weeks) as well as in the fitness state of the subjects. Especially frequency and intensity in combination with the level of hypoxia seem to play a major role in the effectiveness of training in hypoxia. Several approaches have evolved during the last few decades, with “live high – train low” and “live low – train high” being the most popular. Cross-References ▶ Hypoxia, Training ▶ Training, Altitude ambient barometric pressure (PB) or the O2 concentration of the inspired gas. As one ascends to higher altitudes, there is a reduction in PB known as hypobaria. Accordingly, per Boyle’s law (the volume of a gas is inversely proportional to its pressure), as the PB decreases with increasing elevation, the volume of any given gas will increase. As a result of the expanding volume of ambient air at altitude, the partial pressure of each individual gas declines in proportion to the decline in ambient PB. Thus, as the elevation increases, the PO2 (as well as the other gases) decreases resulting in less O2 per liter of air. Consequently, less O2 is presented to the lungs, which results in a reduction of O2 diffusing into the arterial circulation for subsequent utilization by tissues throughout the body. Obviously, the severity of the hypoxia is dependent upon the eventual altitude elevation achieved. At low altitudes (0–4,900 ft, 760–635 mmHg), resting arterial O2 saturation (SaO2) is generally well maintained imparting only a marginal disruption in homeostasis. As one ascends to more moderate altitudes (4,900–9,800 ft, 635–525 mmHg), a slight but significant decrease in resting SaO2 (95–92%) is observed as the inspired PIO2 can decrease to 110 mmHg compared to 159 mmHg at sea level. At high altitudes (9,800–16,000 ft, 525–405 mmHg), ambient PIO2 will decrease further with resting SaO2 approaching 80% and lower. Consequently, the final altitude and degree of hypoxia play a critical role in determining the extent of the physiologic and metabolic responses required to ensure proper tissue oxygenation in response to this environmental disruption to homeostasis. Mechanisms Altitude, Physiological Response ROBERT S. MAZZEO Department of Integrative Physiology, University of Colorado, Boulder, CO, USA Synonyms High elevation; Hypobaric hypoxia; Low inspired oxygen (O2) pressure Definition The main physiological consequence of exposure to high altitude is hypoxia, which can be defined as a reduction in the partial pressure of oxygen in inspired air (PIO2) resulting in hypoxemia (subnormal arterial blood O2 saturation – SaO2). Hypoxia can be induced by decreasing either the Acute Altitude Exposure: The underlying mechanism responsible for the physiological responses observed during acute exposure to high altitude is the direct effect of hypoxia. Adjustments in many physiologic and metabolic systems are necessary to properly respond to the disruption in homeostasis imposed by exposure to high altitude (Fig. 1). These adjustments are regulated, in part, by activation of key components of the neuroendocrine system [4]. Specifically, the autonomic nervous system and the adrenal glands play a major role in both the physiological and metabolic responses. Hypoxia has a direct effect on stimulating epinephrine production and release from the adrenal medulla thereby increasing circulating epinephrine levels. Via b-adrenergic receptors, both heart rate and stroke volume are subsequently increased, both contributing to the increase in cardiac output observed during acute hypoxia. The net result is to increase O2 delivery to critical tissues when the O2 content per liter of blood (CaO2) is reduced as a result of hypoxia. Altitude, Physiological Response A Acute altitude exposure A PIO2 PaO2 Cardiovascular ↑ Heart rate ↑ Stroke volume ↑ Cardiac output Respiratory Metabolic ↑ Ventilatory rate Δ Shift O2-Hb curve ↑ Arterial pH ↑ RMR ↑ Lactate production Neuroendocrine ↑ Adrenal activity ↑ SNS Altitude, Physiological Response. Fig. 1 Effect of acute hypoxia (altitude exposure) on arterial oxygen pressure. Adjustments in several key systems are necessary to respond to this disruption in homeostasis to ensure adequate oxygen delivery to tissues Additionally, epinephrine can contribute to local vasodilation of vascular beds promoting increased blood flow and O2 delivery to the tissues involved. Further, to improve O2-carrying capacity, a reduction in plasma volume (by way of increased urination) occurs in an attempt to concentrate existing red blood cells and increase hematocrit. Activation of both central and peripheral (aortic and carotid bodies) chemoreceptors associated with the respiratory system is the driving force for increases in both ventilatory rate and volume. This response is essential in helping to maintain, as best as possible, O2 pressure in the lungs, and subsequently, in arterial blood. A side effect of this increase in ventilation is a reduction in the partial pressure of carbon dioxide (PCO2) as more CO2 than normal is blown off. This, in turn, results in an increase in arterial pH (alkalosis) initiating a leftward shift in the O2-hemoglobin (O2-Hb) dissociation curve facilitating O2 diffusion and loading from lungs into blood (onto hemoglobin). Upon ascent to altitude, resting metabolic rate (RMR) is elevated above sea-level values and can persist for an extended period of time while remaining at altitude residence. Consequently, the total energy requirement necessary to maintain a stable body weight increases proportionately. In order to avoid a negative energy balance and remain weight stable, this increase in the energy requirement must be coupled with an equal increase in energy intake. However, cachexia (weight loss) is 55 a commonly reported consequence during the initial weeks of high altitude exposure [1]. The weight loss most likely results from a combination of the increase in total energy requirement at altitude coupled with loss of appetite and lower energy intake. While several mechanisms have been suggested that may contribute, in part or combination, to the suppression of appetite at altitude (e.g., SNS activity, leptin, insulin, IL-6), exact causes for this observation remain to be determined. Chronic Altitude Exposure: The classic adaptation associated with acclimatization to chronic altitude exposure is the increase in red blood cell (RBC) numbers [3]. This response is a direct result of the hypoxic stimulus and is secondary to the production of erythropoietin (EPO), a hormone produced primarily by the kidneys that promotes the synthesis of new RBCs in the bone marrow. While the time course and magnitude of change in EPO, and eventual RBC numbers, will vary dependent upon altitude elevation (degree of hypoxia) as well as individual differences, initial changes can be seen within the first week of exposure. These changes, in conjunction with the ventilatory adjustments, result in significant improvements in both arterial oxygen saturation (SaO2) and content (CaO2). Consequently, the physiological stress associated with altitude exposure is partially reduced resulting in a number of physiologic and metabolic adjustments when compared with initial arrival (Fig. 2). Additionally, an increase in RBC 2, 3diphosphoglycerate (2,3 DPG) coupled with a decrease in bicarbonate (kidney excretion) induce a rightward 56 A Altitude, Physiological Response Chronic altitude exposure EPO, RBC, Hct PaO2 Cardiovascular Respiratory Metabolic ↓ Heart rate ↑ Vascular resistance ↑ Blood pressure ↑ Ventilatory rate Δ Shift O2-Hb curve ↓ Arterial pH ↑ RMR ↑ Lactate production Δ Substrate selection Neuroendocrine ↓ Adrenal activity ↑↑ SNS Altitude, Physiological Response. Fig. 2 In response to chronic hypoxia (acclimatization) improvements in oxygen carrying capacity and transport allow for adaptations in various physiologic and metabolic pathways shift in the O2-Hb dissociation curve facilitating O2 unloading from hemoglobin to tissues. A significant elevation in the sympathetic nervous activity is observed during the first week of chronic altitude exposure. This is thought to be responsible for the increase in systemic vascular resistance (a-adrenergic mechanism) and subsequent elevation in arterial blood pressure. Alterations in the sympathoadrenal pathways also contribute to other adjustments made during the acclimatization process, including changes in substrate selection, continued elevation of RMR, and lactate production (particularly during exercise – see below). Exercise Response The physiological responses to exercise at altitude are dependent upon a number of factors. As always, the extent of hypoxia plays a major role in the amount of stress incurred and the extent to which normal homeostasis is disrupted. The addition of the added stress of exercise along with that of hypoxia will have an additive effect that will influence maximal exercise capacity, endurance time until fatigue, and submaximal exercise performance. It is also important to consider the intensity of the exercise bout while at altitude as the relative intensity of an exercise bout plays a major role in the subsequent physiologic and metabolic adjustments (cardiovascular, respiratory, hormonal, etc.) needed to maintain performance _ 2max progressively declines [2]. It is clear that decline VO with increasing altitude elevation. As a result, a given power output represents a greater relative exercise intensity _ 2max ) while at higher eleva(i.e., a higher percentage of VO tions. Consequently, a greater adjustment (physiologic, metabolic) to exercise is required when performing similar exercise tasks at an altitude compared to sea level. This is reflected by greater increases in sympathoadrenal responses, heart rate, cardiac output, ventilatory rate, and lactate production for a given power output when compared to sea-level values (Fig. 1). In individuals that have become acclimatized to altitude, the adaptations made in O2 carrying capacity, transport, and diffusion (described above) allow for a reduced level of exercise stress when compared to acute altitude exposure. As a result, for a given power output, an acclimatized individual will demonstrate lower sympathoadrenal responses, heart rate, cardiac output, ventilatory rate, and lactate production for a given power output when compared to values during acute exposure. A number of these adaptations associated with acclimatization to high altitude may be of potential benefit for the endurance athlete in improving performance at sea level. This is the basic premise for the “Live High–Train Low” paradigm that continues to receive considerable attention [5]. Acclimatization to altitude will result in a number of adaptive responses that improve O2 carrying capacity, transport, and utilization. Specifically, increases in red blood cell volume, total blood volume, and Amino Acid Kinetics improved oxygen delivery to muscle are well documented. Changes in skeletal muscle capillary density and mitochondrial oxidative capacity with acclimatization, while not as consistent, are possible and could result in improvements in endurance performance. It is important to note that these adaptations occur as a result of simply living at high altitudes independent of a training stimulus. The concept of training “low” relates to the observation that training at lower altitudes allows an individual to exercise at a higher absolute workload and power output than would be possible at higher altitudes. Thus, with live high–train low there are two independent stimuli (hypoxia and training) acting to _ 2max , and enhance oxygen delivery and utilization, VO endurance performance. Any performance benefits from altitude adaptations are going to be event specific as participation in events where oxygen delivery and utilization are potentially limiting factors would demonstrate the most benefits to athletes acclimatized to altitude. As there are no changes in key components of anaerobic pathways and an actual reduction in blood bicarbonate levels with altitude acclimatization, very high-intense activities more reliant on non-oxidative fuel sources (power, sprint) would not be expected to show any benefits during return to sea-level performance. degenerative disease is currently considered to be progressive and irreversible with behavioral symptoms usually occurring after the age of 65. The causes of the disease are still under debate, but amyloid plaque formation and neurofibrillary tangles in the brain are two putative pathways leading to the disease. Later stages of the disease results in more extensive memory impairments as well as behavioral problems such as agitation, wandering, and irritability. Cross-References ▶ Neurodegenerative Disease Amenorrhea ▶ Athletic Amenorrhea Amide ▶ Glutamine References 1. 2. 3. 4. 5. Butterfield GE, Gates J, Fleming S et al (1992) Increased energy intake minimizes weight loss in men at high altitude. J Appl Physiol 72:1741–1748 Mazzeo RS, Reeves JT (2003) Adrenergic contribution during acclimatization to high altitude: perspectives from Pikes peak. Exerc Sport Sci Rev 31:13–18 Mazzeo RS, Fulco CS (2006) Physiological systems and their responses to conditions of hypoxia. In: Tipton CM (ed) ACSM’s advanced exercise physiology, Ch 7. Lippincott Williams & Wilkins, Baltimore, pp 564–580 Mazzeo RS (2008) Physiological responses to exercise at altitude: an update. Sports Med 38:1–8 Stray-Gundersen J, Chapman RF, Levine BD (2001) “Living hightraining low” altitude training improves sea level performance in male and female elite runners. J Appl Physiol 91:1113–1120 2-Amino-4-Carbamoylbutanoic Acid ▶ Glutamine 2-Aminoglutaramic Acid ▶ Glutamine a-amino Carboxylic Acid Alzheimer’s Disease A neurodegenerative disorder of aging characterized by progressive memory impairment as the result of the dysfunction and death of nerve cells in the brain, particularly those in the temporal and frontal lobes. The most common form of dementia that results in memory and cognitive impairments during late adulthood. The A ▶ Amino Acids Amino Acid Kinetics ▶ Metabolism, Protein 57 A 58 A Amino Acid Oxidation R Amino Acid Oxidation Amino acid oxidation is the process by which amino acids are used as a fuel source to produce ATP. The amino group is removed to convert the amino acid into an a-keto acid that is incorporated into the tri-carboxylic acid cycle for eventual production of ATP within the mitochondria. H2N C COOH H Amino Acids. Fig. 1 Schematic of the general structure of an amino acid Amino Acids. Table 1 List of essential and nonessential amino acids Amino Acids Essential a JARED M. DICKINSON, BLAKE B. RASMUSSEN Department of Nutrition & Metabolism, Division of Rehabilitation Sciences, University of Texas Medical Branch, Galveston, TX, USA Nonessential Histidine Alanine Isoleucine Arginine Leucine Asparagine Lysine Aspartic acid Methionine Cysteine Phenylalanine Glutamic acid Synonyms Threonine Glutamine a-amino carboxylic acid; Protein building blocks Tryptophan Glycine Valine Proline Definition An amino acid is a molecule in which a central carbon (C) atom is bound by an amino group (NH2), a carboxyl group (COOH), a hydrogen atom (H), and an organic side chain (R) (Fig. 1). Amino acids are differentiated from one another by the structure of the organic side chain, which is unique to a given amino acid and also defines the specific properties of that amino acid. There are 20 common amino acids that are utilized as the “building blocks” for ▶ protein, such that the linking of amino acids in a precise linear sequence serves as the foundation for the structure and function of a protein. Further, amino acids are categorized as either nonessential or essential. Proper physiological concentrations of nonessential amino acids can be achieved through de novo synthesis, whereas physiological concentrations of essential amino acids cannot be maintained through de novo synthesis and must be introduced in the diet. Of the 20 common amino acids, 9 are considered essential and 11 nonessential (Table 1). In addition to the 20 common amino acids classified as standard, amino acids can undergo post-translational modifications prior to the formation of a protein. These amino acids are referred to as nonstandard amino acids. Mechanism of Action Amino acids most notably serve as the building blocks for protein. Specifically, amino acids are joined together via peptide bonds in a precise linear sequence to form a single polypeptide chain. Through ensuing processes, one or Serine Tyrosine a Essential to infants more of these polypeptide chains can be utilized to construct a protein, and the specific amino acid sequence of each polypeptide chain provides the foundation of the protein’s structure and function. In fact, removing or replacing a single amino acid in the precise sequence can substantially interfere with the proper functioning of the protein or even render the protein completely inactive. The sequence of amino acids in a given polypeptide is ultimately determined by the base sequence of specific regions of DNA, referred to as ▶ genes. This genetic information is communicated within the cell through the processes of ▶ transcription and ▶ translation, and the production of a single polypeptide/protein requires collaboration between numerous molecules, including DNA, messenger RNA (mRNA), transfer RNA (tRNA), ▶ ribosomes, and several enzymes. Not only do amino acids serve as the foundation for protein structure, but changes in amino acid availability have a potent effect on protein turnover, which is the concurrent processes of protein synthesis and breakdown. Specifically, an increase in amino acids availability, such as that experienced during a meal, rapidly and transiently stimulates an increase in the rate of protein synthesis, whereas protein breakdown appears to decrease slightly Amino Acids A 59 A - Amino Acids + Amino Acids hVps34 Uncharged tRNA ? + ? mTORC1 Autophagy ? GCN2 Protein Breakdown 4E-BP1 eIF2α eIF4F S6K1 rpS6 eEF2 Global Protein Synthesis Translation Initiation Translation Elongation Protein Synthesis Amino Acids. Fig. 2 Simplified schematic of the effect of amino acid availability on protein metabolism. Low levels of amino acids (left) decrease global rates of protein synthesis through increased activity of general control nonrepressed 2 (GCN2). High levels of amino acids (right) increase protein synthesis rate by stimulating the activity of mammalian target of rapamycin complex 1 (mTORC1). In addition, stimulation of mTORC1 by high levels of amino acids appears to decrease autophagy, which contributes to a reduction in protein breakdown: tRNA, transfer RNA; eIF2a, eukaryotic initiation factor 2 alpha; hVps34, human vacuolar protein sorting-34; 4E-BP1, 4E binding protein 1; S6K1, p70 ribosomal S6 kinase 1; eIF4F, eukaryotic initiation factor 4F; rpS6, ribosomal protein S6; eEF2, eukaryotic elongation factor 2 (Fig. 2). The increased availability of amino acids (primarily essential amino acids) stimulates an increase in mammalian target of rapamycin complex 1 (mTORC1) activity, which is a key nutrient sensor and regulator of protein metabolism [1, 2]. mTORC1 subsequently phosphorylates two important direct downstream targets, ribosomal protein S6 kinase 1 (S6K1) and 4E binding protein 1 (4E-BP1), that facilitates a variety of downstream effects that ultimately enhance translation initiation and elongation. In addition, mTORC1 activation in response to increased amino acid availability also appears to decrease protein breakdown, and thus the liberation of free amino acids, which may in part be due to a decrease in autophagy as a result of human vacuolar protein sorting-34 (hVps34) signaling to mTORC1 (Fig. 2). On the other hand, a decrease in amino acid availability has been shown to slow the rate of protein synthesis. Specifically, deficient levels of amino acids lead to an increase in uncharged tRNA that in turn bind to and activate general control nonrepressed 2 (GCN2) kinase. Subsequently, GCN2 kinase phosphorylates eukaryotic initiation factor 2a (eIF2a), which slows the rate of global protein synthesis [3] (Fig. 2). As a consequence of their impact on the regulation of protein metabolism, amino acids have a tremendous role in growth and development. Amino acids also serve in the maintenance of energy stores and energy substrate within the body. For instance, amino acids are necessary for the production of nucleotides, which not only form the structure of RNA and DNA and serve as cellular signaling molecules, but they also act as chemical energy stores in the form of ATP and GTP. Moreover, the importance of amino acids in terms of bioenergetics becomes severely important during stress, malnutrition, and injury conditions. Under such conditions, the carbon skeleton of many amino acids can be utilized to produce acetyl-CoA, which in turn can be oxidized via the Krebs cycle and electron transport chain for the production of ATP. Additionally, during these conditions several amino 60 A Amino Acids acids serve as major hepatic gluconeogenic substrates and can be utilized to provide energy substrate to several tissues including the brain and immune cells. In addition to those addressed above, amino acids and their metabolites are imperative to numerous other medically relevant biological processes. For instance, glutamine serves as a major energy substrate for cells of the immune system and is involved in reducing inflammation. Arginine serves as the precursor for nitric oxide, an important signaling molecule associated with mitochondrial biogenesis, blood flow regulation, and cardiovascular health. In fact, several amino acids are utilized as biosynthetic molecules for a variety of products that serve a multitude of biological functions, including but not limited to: hormones, coenzymes, oxidative stress response, ammonia detoxification, neurotransmitters, porphyrins, immune function, signaling molecules, reproduction, metabolic intermediates, and energy substrates [4]. Clinical Use Due to the diversity of metabolic pathways that require the use of one or more amino acids, disturbances in the physiological levels of many amino acids can lead to disruptions in several biological processes. For instance, high physiologic levels of amino acids can induce insulin resistance, which chronically can lead to a multitude of debilitating clinical conditions. Similarly, deficiencies in some amino acids can impair growth, compromise proper immune function, and lead to development of cardiovascular complications. Maintenance of appropriate amino acid levels can be achieved either through the diet or through de novo synthesis, dependent upon whether the specific amino acid is classified as essential or nonessential. However, under some circumstances de novo synthesis of certain amino acids usually classified as nonessential may not provide optimal levels, and thus supplementation is required. For example, arginine concentration is substantially reduced during various clinical conditions, including burn injury, sepsis, and trauma. Under such circumstances, not only is arginine supplementation necessary to restore proper physiological levels of the amino acid, but supplementation of arginine also appears to improve the healing/immune response. In fact, arginine supplementation has also been suggested as a useful supplement in a variety of conditions such as obesity, diabetes, and cardiovascular disease [4]. It is very well established that numerous clinical conditions are associated with muscle wasting. Not only does this loss of muscle mass impair physical function, but because skeletal muscle serves as the largest reservoir of amino acids in the body, muscle atrophy is also detrimental to a multitude of amino acid dependent biological processes that are imperative for healing, immune function, and recovery. Increasing amino acid availability, either through infusion or ingestion, promotes an anabolic environment in skeletal muscle and therefore represents a potential countermeasure to conditions of muscle wasting that can easily be employed in a majority of clinical settings. The ability for amino acids to increase muscle protein synthesis is driven primarily by an increased availability of essential amino acids. Further, both young and older individuals appear to have a similar increase in muscle protein synthesis when a large dose (>15 g) of essential amino acids is ingested. In contrast, older adults are less sensitive to a lower amount of essential amino acids. The discrepancy between younger and older individuals in their muscle protein anabolic response to amino acid availability is likely to be important since aging itself results in reductions in muscle size and function. Future research is clearly warranted to more precisely define proper guidelines for use of amino acid supplementation with various clinical conditions. The clinical value of increased amino acid availability is also observed when coupled with exercise. Specifically, ingesting essential amino acids shortly following a bout of resistance exercise stimulates muscle protein synthesis to a much greater extent than that elicited independently by each stimulus [2], suggesting that increased amino acid availability following exercise may aide in muscle recovery and growth. Moreover, coupling amino acid ingestion and exercise may also serve an important role in the maintenance of muscle mass with aging, as the blunted anabolic response following resistance exercise in older adults can be restored by providing essential amino acids shortly after exercise. Diagnostics Important insight into the in vivo metabolic kinetics of amino acids can be examined with the use of amino acid tracers. Amino acid tracers are amino acids that contain either a radioactive or a stable ▶ isotope (depending on the specific measurement) that differentiates the tracer from the most common form of the amino acid by mass (and the presence of radiation emission for radioactive isotopes), but does not alter the chemical or functional identify of the amino acid. The difference in mass, and/or the emission of radiation, allows investigators and clinicians to follow the fate of the amino acid in a variety of biological processes, which can serve as a unique diagnostic tool for many diseases/conditions. For instance, a variety of radiolabeled amino acids have been utilized to identify cancerous tumors. Specifically, cancer cells display an accelerated rate of protein synthesis and AMP-Activated Protein Kinase amino acid transport, which leads to accumulation of an infused radiolabeled amino acid within the cell. The release of emissions from the accumulated radiolabeled amino acid is then measured with positron emission tomography to visualize the tumor [5]. Amino acid tracers can also be utilized to examine muscle protein metabolism following various therapeutic interventions. Monitoring muscle protein metabolism provides useful insight into the anabolic response of skeletal muscle to a given intervention (i.e., exercise or nutrition) and thus provides important information as to the usefulness of a given intervention to promote muscle mass gain or attenuate muscle loss. Such insight is clinically significant due to the loss of muscle mass that is associated with a variety clinical conditions and the importance of muscle mass as an amino acid reservoir for numerous medically relevant biological processes. A Definition AMPK, a trimeric serine/threonine ▶ protein kinase, acts as a cellular energy gauge [1]. Association of AMP with the g ▶ adenine nucleotide binding subunit ▶ allosterically activates AMPK and appears to make the catalytic a subunit less susceptible to ▶ dephosphorylation of its activation site. The b subunit has been suggested to play a role in sensing of glycogen levels by AMPK [1]. Basic Mechanisms This review focuses on effects of AMPK activation in skeletal muscle. However, AMPK functions in a wide variety of tissues. For example, AMPK suppresses fatty acid synthesis in ▶ lipogenic tissues, stimulates feeding behavior by actions in hypothalamus, and might play a role in oxygen sensing in the carotid body [1]. Activation of AMPK References 1. 2. 3. 4. 5. Kimball SR (2007) The role of nutrition in stimulating muscle protein accretion at the molecular level. Biochem Soc Trans 35:1298–1301 Drummond MJ, Dreyer HC, Fry CS, Glynn EL, Rasmussen BB (2009) Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling. J Appl Physiol 106:1374–1384 Hundal HS, Taylor PM (2009) Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling. Am J Physiol Endocrinol Metab 296:E603–E613 Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37:1–17 Jager PL, Vaalburg W, Pruim J, de Vries EG, Langen KJ, Piers DA (2001) Radiolabeled amino acids: basic aspects and clinical applications in oncology. J Nucl Med 42:432–445 AMP Kinase ▶ AMP-Activated Protein Kinase AMP-Activated Protein Kinase STANLEY ANDRISSE, JONATHAN S. FISHER Department of Biology, Saint Louis University, St. Louis, MO, USA Synonyms Adenosine 50 -monophosphate-activated protein kinase; AMP kinase; AMPK Muscle contractions activate AMPK in crucial support of exercise performance. For example, mice that express a ▶ dominant negative form of AMPK (DN-AMPK) that prevents AMPK activation have a substantial reduction in exercise capacity [2]. In resting skeletal muscle, ATP levels are about 800 times higher than AMP concentrations. During metabolic stress such as muscle contractions, the reaction catalyzed by adenylate kinase (2 ADP ! ATP + AMP) increases AMP concentration by approximately tenfold. In contrast, ATP levels generally do not fall during exercise except under extreme conditions. Thus, in working muscle, a large increase in the AMP-to-ATP ratio promotes binding of AMP to the g subunit and activation of AMPK. Calcium- and cytokine-dependent pathways that are independent of changes in cellular energy status also activate AMPK. Glucose Transport Since the 1990s, muscle biologists have hypothesized that activation of AMPK in contracting skeletal muscle causes the increase in glucose uptake into muscle during exercise [1]. However, we now know that expression of DN-AMPK in mouse skeletal muscle does not prevent stimulation of glucose transport by treadmill running [2], despite previous findings that DN-AMPK blunts glucose transport after electrically stimulated muscle contractions [3]. It appears that a role of AMPK in regulation of glucose transport depends on the duration of the contraction pattern. For example, glucose transport in mouse muscles expressing DN-AMPK does not increase during the first 15 min of electrically stimulated muscle contractions but then reaches the same levels as in wild-type mice after 20 min of contractions [4]. Using different 61 A 62 A AMP-Activated Protein Kinase ▶ transgenic models of AMPK deficiency in skeletal muscle, other groups have found no requirement for AMPK in stimulation of glucose transport by contractions. Taken together, these data suggest that AMPK plays a nonessential part in stimulation of glucose transport in skeletal muscle during exercise. Despite the apparently limited role of AMPK in regulation of glucose transport during muscle contractions, activation of AMPK in the absence of muscle contractions appears sufficient to stimulate glucose transport in skeletal muscle. For example, ▶ AICAR, a precursor of an AMP analog, stimulates glucose transport in skeletal muscle. Likewise, expression of a chronically active form of the AMPK catalytic subunit in cultured skeletal muscle cells increases basal glucose transport. On the other hand, mutations of the g subunit of AMPK that cause chronic activation of AMPK do not enhance basal glucose transport. Therefore, roles of AMPK in stimulation of glucose transport remain to be worked out. Unresolved issues include the subtle differences in transgenic animal models and the timing of AMPK effects during exercise. In addition, whether activation of AMPK is sufficient to stimulate glucose transport in skeletal muscle needs further clarification. Fatty Acid Uptake and Oxidation in Skeletal Muscle Over 15 years of studies have shown an association of AMPK activation with the increase in fatty acid oxidation that occurs during muscle contractions [1]. For example, AICAR stimulates fatty acid oxidation in skeletal muscle. On the other hand, muscle-specific deletion of LKB1, which is an activator of AMPK and a dozen other members of the AMPK-related kinase family, prevents activation of AMPK but does not interfere with contraction-stimulated fatty acid oxidation [3]. Further, expression of DN-AMPK in mouse muscle does not affect whole body fatty acid oxidation during exercise. To complicate matters, DN-AMPK expression in skeletal muscle prevents contraction-stimulated fatty acid oxidation in some studies but not others. Thus, while it seems likely that activation of AMPK suffices to stimulate fatty acid oxidation, the conditions under which AMPK plays a role in fatty acid oxidation in skeletal muscle remain to be defined. Likewise, mixed results exist regarding a possible action of AMPK in regulation of fatty acid uptake during muscle contractions. Using the DN-AMPK model, some groups find no requirement for AMPK for an increase in fatty acid uptake during contractions. However, another group has reported that AMPK plays a necessary role in stimulation of fatty acid uptake during extended contraction protocols but not early in a sequence of contractions [4]. Mitochondrial Biogenesis and Glucose Transporter Abundance AICAR injections in rats or incubation of isolated skeletal muscle with AICAR causes increases in activity or abundance of marker enzymes of mitochondrial biogenesis and also increased levels of GLUT4, the insulin- and contraction-responsive glucose transporter in skeletal muscle. In contrast, AMPK appears nonessential to exercise training-related increases in mitochondrial gene or protein expression or GLUT4, as these adaptations occur in LKB1-deficient or AMPKa2 knockout mice [3]. Protein Synthesis In rodents and humans, skeletal muscle protein synthesis is reduced during exercise/muscle contraction and by treatment with AICAR. Protein synthesis is regulated by mammalian target of rapamycin complex 1 (mTORC1), a protein kinase that manages mRNA translation initiation via phosphorylation of key mediators of mRNA translation [1]. The increase in muscle cross-sectional area, also known as hypertrophy, associated with resistance exercise is largely due to enhanced protein synthesis via activation of mTORC1 [1]. AMPK’s reduction of mTORC1 activity is one of several proposed mechanisms by which exercise lowers protein synthesis [1]. Oddly enough, AMPK appears to display its inhibitory effects on mTORC1/protein synthesis during both endurance and resistance exercise; however, immediately following resistance exercise, AMPK, although still elevated, does not restrain mTORC1 activity. It has been shown that swimming exercise causes an increase in the sensitivity of ▶ System A amino acid transport to insulin-like growth factor 1 in skeletal muscle. However, it remains unknown whether AMPK plays a role in this process and whether the increased amino acid influx would be sufficient to stimulate mTORC1. Interestingly, in animals expressing DNAMPK in skeletal muscle, protein synthesis remains suppressed during skeletal muscle contraction, suggesting that AMPK is not required for inhibition of protein synthesis during exercise [3]. Lifespan Caloric restriction increases maximal lifespan in a variety of organisms, including flies, worms, mice, rats, and dogs. Interestingly, several effects of caloric restriction, such as activation of sirtuins, inhibition of mTOR, and mitochondrial biogenesis, are also effects of AMPK activation [1]. Indeed, worms that lack AMPK do not display a caloric restriction effect on maximal lifespan. Interestingly, wheel running exercise, that would activate AMPK in skeletal muscle, increases average but not maximal life span in rats. AMP-Activated Protein Kinase This suggests that if AMPK mediates extension of maximal lifespan during caloric restriction, the effect occurs in a tissue other than skeletal muscle. Exercise Intervention Exercise and Increased Insulin Action and glycogen storage [3, 5]. For example, after exercise, a physiological level of insulin produces a twofold higher stimulation of glucose uptake compared to glucose transport into non-exercised muscle. In rat skeletal muscle and cultured skeletal muscle cells, activation of AMPK by AICAR mimics the increased insulin action that occurs after exercise. Moreover, AICAR infusion in humans increases insulin-stimulated glucose uptake. Expression of a constitutively active a1 subunit of AMPK also causes increased insulin action in cultured muscle cells. These data and others suggest that activation of AMPK is sufficient to increase insulin sensitivity in skeletal muscle. Intriguingly, several compounds and ▶ adipokines that activate AMPK, including metformin, rosiglitazone, leptin, and adiponectin, have antidiabetic effects. It remains ion ns te ex of ma xim for an sp life nt icie uff al ts activation of AMPK in skeletal muscle no g an luco d f se sti att y a trans mula cid po tio up r t e n of req tak arl uir e l y in ed ate e for in xerc eff ex ec erc ise ts ise of ? co ntr ac tio ns on Changes in lifestyle over the past several decades, such as a decrease in physical activity and increased consumption of calorie-dense foods, have contributed to a dramatic, world-wide rise in the prevalence of non-insulindependent diabetes mellitus, or type II diabetes. Subjects with type II diabetes display impaired insulin-stimulated glucose transport into skeletal muscle. Fortunately, exercise increases both insulin-stimulated glucose transport A sufficient for • stimulation of glucose transport, fatty acid uptake and oxidation, GLUT4 expression, and mitochondrial biogenesis • increased IGF1-stimulated amino acid transport and insulin-stimulated glucose uptake • inhibition of protein synthesis AMP-Activated Protein Kinase. Fig. 1 AMPK actions in skeletal muscle. AMPK can be experimentally activated by chemicals such as AICAR or therapeutically activated by drugs such as metformin. AMPK is also activated during muscle contractions by factors including an increase in the AMP:ATP ratio or a rise in cytosolic calcium ion availability. Activation of AMPK in skeletal muscle appears to be sufficient to stimulate glucose transport, fatty acid uptake and oxidation, GLUT4 glucose transporter expression, and mitochondrial biogenesis. Activation of AMPK also is sufficient to increase stimulation of amino acid transport by insulin-like growth factor 1 (IGF1), increase stimulation of glucose uptake by insulin, and inhibit protein synthesis. However, work with transgenic animals lacking AMPK activity in skeletal muscle suggests that AMPK is not required for any of the above actions in response to muscle contractions. Possible exceptions migh-t be time-dependent requirements for AMPK in regulation of glucose transport and fatty acid uptake during exercise 63 A 64 A AMPK to be determined, however, whether AMPK is required for increased insulin action in skeletal muscle after exercise. Summary It seems clear that activation of AMPK can produce healthful effects in skeletal muscle, such as enhanced glucose transport, increased fat oxidation, and mitochondrial biogenesis (see Fig. 1 for summary). However, future study should be done to fully elucidate the sufficiency of and/or requirement for AMPK in the acute and chronic effects of skeletal muscle contraction. It seems that AMPK’s role in muscle contractions could be dependent on exercise duration or intensity, but this area needs further examination. While many of the mediators of AMPK’s effects in skeletal muscle have been described [1, 3], novel effectors are likely to be discovered. Finally, it needs to be determined which proteins work with – or instead of – AMPK in orchestrating the consequences of skeletal muscle contraction or treatment with AICAR. Cross-References ▶ Diabetes Mellitus ▶ Diabetes Mellitus, Prevention ▶ Diabetes Mellitus, Sports Therapy ▶ Energy Metabolism ▶ Insulin Resistance ▶ Insulin-like Growth Factor ▶ Metabolism, Carbohydrate ▶ Metabolism, Lipid ▶ Metabolism, Protein ▶ Mitochondrial Biogenesis References 1. 2. 3. 4. 5. Hardie DG (2011) Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc 70:92–99 Maarbjerg SJ, Jorgensen SB, Rose AJ et al (2009) Genetic impairment of AMPKa2 signaling does not reduce muscle glucose uptake during treadmill exercise in mice. Am J Physiol Endocrinol Metab 297: E924–E934 Jensen TE, Wojtaszewski JF, Richter EA (2009) AMP-activated protein kinase in contraction regulation of skeletal muscle metabolism: necessary and/or sufficient? Acta Physiol (Oxf) 196:155–174 Abbott MJ, Bogachus LD, Turcotte LP (2011) AMPKa2 deficiency uncovers time-dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle. J Appl Physiol 111:125–134 Turcotte LP, Fisher JS (2008) Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise. Phys Ther 88:1–18 AMPK ▶ AMP-Activated Protein Kinase Amputation Amputation is a congenital or acquired disability which results in the loss of one or more limbs. Amputations of the upper or lower extremities are performed as a result of trauma, peripheral vascular disease, type II diabetes, tumors, and other medical conditions. Amyloid A 40–42 amino acid peptide that aggregates and damages neurons in the brain in Alzheimer’s disease. Amyotrophic Lateral Sclerosis ▶ Neurodegenerative Disease Anabolic Metabolic reactions that construct molecules from smaller units and require energy. They tend toward building up organs and tissues by favoring growth and differentiation of cells. Anabolic Androgens ▶ Anabolic Steroids Anabolic Hormones Anabolic hormones are those hormones required to stimulate protein synthesis, either directly or indirectly. This group of hormones includes: testosterone, Growth hormone, insulin and the IGFs. Anabolic processes, triggered by these hormones culminate in the growth and differentiation of tissues, ultimately increasing body size as is the case in skeletal muscle hypertrophy. These hormones may be steroid (testosterone) or peptide (IGF and GH) hormones acting via nuclear or cell surface receptors, respectively. The processes of protein synthesis initiated by Anabolic Steroids anabolic hormones are energy requiring, with the fuel source in the form of adenosine tri-phosphate (ATP). It is not cheap (metabolically) to generate or maintain tissue mass, therefore it is unlikely that an organism will lay down new protein unless it requires that new mass to function. During puberty, males lay down more muscle than females as a consequence of elevated testosterone production. The abuse of anabolic steroids therefore, will culminate in excess hypertrophy of skeletal muscle, beyond what may have occurred naturally. A Around 1930 androgenic–anabolic steroids (AAS) were developed. AAS are drugs derived from the male sex hormone testosterone. Although many efforts have been undertaken to dissipate the androgenic and anabolic effects, until now this was not successful. Therefore, all AAS still have both androgenic and anabolic effects. In adults, the androgenic properties stimulate masculinization of the human body including growth of genital size, male body hair distribution, and increase of libido and potency. The anabolic effects refer to building effects on several organ systems, e.g., muscle and bone growth and enlargement of the heart, kidney, and prostate. Steroids possessing high affinity to these receptors are categorized as (strong) androgens (e.g., metenolone, 19-nortestosterone), whereas others show only low affinity to these receptors (e.g., fluoxymetholone, stanozolol) and therefore are called weak androgens. Moreover, some AAS (e.g., oxymetholone) do not bind to a receptor at all but exert their action via other routes. Another pathway is mediated by glucocorticoid receptors. AAS may bind to these receptors and exert anti-glucocorticoid actions by counteracting the glucocorticoid-induced breakdown of proteins, resulting in an anti-catabolic effect. The hematologic system is considered to be influenced by two main pathways: stimulation of erythropoiesis and erythropoietin synthesis in the kidney. At the muscular level, AAS may induce muscle hypertrophy directly and indirectly via the formation of new muscle fibers. A key role is assigned to satellite cells that are progenitor cells of muscle. AAS increase the number of satellite cells and accelerate the incorporation of these cells in preexisting muscle fibers. The distribution of androgen receptors, that are located predominantly in neck and shoulder girdle muscles resulting in largest muscle growth at these body sites, is also of importance. The cardiovascular system may be affected by several pathways. Firstly, AAS may enhance the activity of the enzyme hepatic triglyceride lipase. This induces lowering of HDL-cholesterol and elevation of serum LDLcholesterol serum concentrations, resulting in a decrease of regression of atherogenic plaques in vessel walls. Secondly, AAS affect the haemostatic system unfavorably, especially platelet aggregation, which includes an increased risk for the occurrence of thrombosis. Thirdly, nitric oxide may be of importance. In smooth muscles and arteries, nitric oxide has the property to act as an endothelial-derived relaxing factor. AAS may affect nitric oxide leading to reduced relaxation or induction of vasospasm. Finally, AAS may also directly injure myocardial cells and cause cell death. Mechanisms of Action Clinical Use Anabolic Steroids FRED HARTGENS Departments of Epidemiology and Surgery, Maastricht University Medical Centre, Research school CAPHRI, Sports Medicine Centre Maastricht, Maastricht, The Netherlands Synonyms Anabolic androgens; Male sex hormones Definition AAS exert their action via several pathways. These substances cross the cell membrane and bind to androgen receptor. The steroid-receptor complex exerts their action in the cell nucleus. Other intracellular routes run via the enzymes 5-a-reductase and aromatase. Under normal circumstances, 5-a-reductase plays an important role in the expression of the sex hormones. The enzyme aromatase converts AAS into female sex hormones and is, therefore, mainly active in the presence of excessive concentrations of AAS (Fig. 1). Therapeutic Use of AAS The main indications for AAS treatment are androgen deficiency states, lichen sclerosis and dystrophy of the vulva, postmenopausal osteoporosis, aplastic anemia and anemia in chronic renal insufficiency. New indications are subject to research yet, and include diseases characterized by catabolic states like COPD, HIV/AIDS, and rheumatic disease conditions. 65 A 66 A Anabolic Steroids Cell nucleus Estro gens E REC E - REC Aromatase Testos terone Testos terone T REC T - REC REC DHT - REC 5-alpha-reductase DHT DNA Anabolic Steroids. Fig. 1 Mechanism of action. T testosterone, DHT dihydrotestosterone, E estradiol, Rec receptor, DHT-rec dihydrotestosterone-receptor complex, T-rec testosterone-receptor complex, E-rec estradiol-receptor complex (Mis-)use of AAS in Sport Fat Mass For many years, the laboratory statistics of the International Olympic Committee (IOC) indicate that AAS are by far the most detected substances at doping analyses. AAS count for over 40% of positive tested urine samples. Moreover, in elite sports not under responsibility of the IOC, many athletes have been found to have used these substances. In some professional sports, especially in strength sports and American football, up to 68% of athletes admitted to have used these drugs during their sports career. Abuse of AAS by amateur and recreational sportsmen is also widespread. In some sports (especially bodybuilding and power lifting) up to 67% of the athletes used these substances at least once. In addition, in college and high school athletes, misuse of AAS is of great concern, especially in the USA with prevalence rates of 12–15%. The fat-reducing properties of AAS are well demonstrated in healthy males. The main sites where fat reduction may be observed are the trunk, limbs, and intermuscular adipose tissue. However, in men under physical training, both novice and experienced, no reduction of fat mass has been observed so far. Effects on Body Composition Fat-Free Mass AAS posses strong fat-free mass stimulating properties. For many years, it was assumed that only experienced athletes participating in a strength training program were susceptible. However, recent research revealed that AAS may also stimulate fat-free mass in non-training subjects. Fat-free mass may increase by 2–5 kg, although gains up to 9 kg have been observed. The effects on fat-free mass show a strong dose–response relationship, whereas mode of application and duration of administration seem to be of lesser importance. Body Mass It is well established that AAS increase body mass. Increments up to 9 kg have been observed after 6 months polydrug AAS abuse in experienced strength athletes. Even in healthy non-training males the administration of testosterone enanthate for 10–20 weeks lead to comparable body mass changes. However, the average mass gain may be considered between 2 and 5 kg, in experienced as well as in novice athletes. Skeletal Muscle In healthy males, the increase of fat-free mass can be ascribed to stimulation of muscle mass. Examination by ultrasonography and magnetic resonance imaging (MRI) elucidated that muscle mass of selected body parts may increase dramatically under AAS administration. Testosterone enanthate administration (600 mg/week, intramuscularly) for 20 weeks revealed increments up to 15% Anabolic Steroids of thigh muscle volume in non-training males determined by MRI measurements. Moreover, in experienced weightlifters receiving 3.5 mg testosterone enanthate per kilogram body weight, intramuscularly, for 12 weeks muscle mass of the triceps brachii muscle increased even by 31.4%. The muscle mass increments can be attributed to enlargement of muscle fibers, although there are indications that the number of muscle fibers may also increase. The drugs used and methods of administration may influence outcome. In strength athletes participating in their regular strength training program, nandrolone decanoate administered in high therapeutic doses, was not able to affect muscle fiber dimensions. On the other hand, in strength athletes, polydrug administration in supratherapeutic doses lead to the largest alterations of muscle fiber dimensions. Muscle fiber growth after shortterm (8–10 weeks) administration was less pronounced compared to long-term administration during 24 weeks, with the longer duration having an advantage of approximately 50%. In a non-training study in healthy young males, high doses of testosterone enanthate for 20 weeks lead to enlargement of individual muscle fibers in a dosedependent fashion. Administration of 50 mg/week increased cross-sectional area of slow twitch muscle fibers by 20%, while 600 mg/week counted for an increment of fiber dimension of 50%. A treatment. However, in non-training men higher doses of AAS are required to obtain comparable strength improvements than in males receiving AAS and concomitantly participating in a strength training program. The effects of different drugs on strength may differ, and a dose–response relationship is identified. Duration of drug administration seems of lesser importance. Endurance Based on the putative hematological effects it has been proposed that AAS might improve endurance performance. However, all studies in endurance athletes (including runners, cyclists, cross-country skiing) undergoing endurance training were not able to determine any effect of AAS on performance or aerobic capacity. On the contrary, a remarkable observation in two studies was that in strength athletes AAS administration improved aerobic capacity significantly while the subjects did not train their endurance capacity at all. Until now the explanation for this finding remains to be established. Mixed Strength-Endurance Only one study investigated the effects of AAS on a combined strength-endurance sports activity, i.e., canoeing, and observed improvements of strength (+6%) and canoeing performance (+9%) after 6 weeks OralTurinabol (Dehydrochlormethyltestosterone) usage. Recovery Body Water Effects on Performance Due to the anabolic and anti-catabolic properties of AAS it has been speculated that these substances might enhance recovery in athletes. This effect has been found in animals, but the results in human studies investigating physiological indicators of recovery and performance as well as indirect parameters of recovery (e.g., response of enzymes like creatine phosphokinase and aspartate aminotransferase, heart rate response, steroid hormone responses, lactate response) are inconclusive yet. Strength Side Effects In many sports, muscle strength is an important factor for success. Until recently, it was assumed that AAS might enhance strength only in experienced and well training strength athletes. This was mainly based on the results of two identical studies by the same researchers, in which only the population (experienced strength athletes and non-strength trained students, respectively) under investigation differed. In the last decades, this theory was abandoned when several well-designed studies demonstrated that in novice athletes and even in non-training humans skeletal muscle strength may increase under AAS AAS have the potential to affect many organs system and therefore may induce untoward effects as well. The most pronounced side effects include the reproductive system, the cardiovascular system, the brain, and liver function. Recent investigations showed that the increase of body mass may be attributed to increments of total muscle mass since hydration of fat-free mass was unaffected by AAS. This is in contrast to previous observations indicating that an increase of blood volume and/or water retention was responsible for the body mass increase. Reproductive System AAS exert suppressive effects on the hypothalamepituitary-gonadal axis. This will lead to lowering of serum levels of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The male athlete may experience alterations of libido and eretile function, 67 A 68 A Anabolic Steroids testicular athropy, subfertility, gynaecomastia, and prostate dysfunction. Untoward effects in females consist mainly of menstrual irregularities, breast atrophy, clitoris hypertrophy, and masculinization (e.g., hirsutism). Cardiovascular System The cardiovascular risk profile may change unfavorably and heart muscle may be affected, partially dependent on the drugs used. AAS suppress serum concentrations of HDL-cholesterol and its subfractions (HDL2- and HDL3-cholesterol), apolipoprotein-B1 levels, and lipoprotein(a), whereas serum levels of LDL-cholesterol and apolipoprotein-A levels increase. AAS do not seem to influence serum triglycerides levels and the effects on serum total cholesterol are inconsistent. The effects of AAS on blood pressure are inconclusive yet, but indicate that androgenic substances may affect blood pressure more than anabolic agents. Elevation of blood pressure may occur in susceptible persons, but do not exceed medical reference values. AAS may affect heart function and structure at the cellular level shortly after starting AAS administration as has been well established in animal studies. In male AAS-using athletes, cross-sectional echocardiographic examinations revealed larger left ventricular wall thickness, posterior wall thickness, and interventricular septum thickness compared to non-using counterparts, and additionally, diastolic function may be impaired. However, such alterations could not be observed in short-term prospective studies until now. Therefore, the influence of AAS on heart function remains to be established. Liver The hazardous effects of AAS on the hepatic system are well recognized from patient studies. The most pronounced observations include subcelllular changes of hepatocytes, impaired excretion function, cholestasis, peliosis hepatis, hepatocellular hyperplasia, and carcinomata. The most liver toxic substances are the 17-alpha-alkylated steroids, like oxymetholone and methyltestosterone. On the other hand, in athletic populations such untoward effects on the liver could not be confirmed after short-term (weeks to months) use of AAS. Serum liver function enzyme alterations under AAS seem to be limited. Slight transient elevations of ALAT and ASAT may occur after taking oral AAS, whereas other liver enzymes remain unaffected. Nevertheless, the occurrence of liver disease should be of great concern in athletes abusing AAS, especially in those administering these substances for prolonged periods. Psyche and Behavior Psychological state and behavior are affected by AAS use. Most reported are increased irritability, greater drive to train, and several (minor) mood disturbances. Serious psychiatric problems may occur only in a few AAS users and is associated with abuse of higher doses of AAS administration. The most pronounced alterations are increased aggression and hostility, mood disturbances (e.g., mania, psychosis, depression) and criminal behavior, including assault and homicide. Athletes in cosmetic sports are dissatisfied with their body and expose a narcissistic personality that may trigger starting AAS abuse. Moreover, AAS dependence and withdrawal effects are seen in a substantial number of AAS abusers. Other In case reports, a large number of side effects have been associated with AAS abuse in athletes, including disturbance of glucose metabolism and thyroid function, occurrence of acne vulgaris and fulminans, sebaceous glands alterations, reduction of immune function, myocardial infarction, suicidal efforts, musculoskeletal injuries, bladder and prostate dysfunction. Furthermore, the formation of tumors (e.g., renal cell carcinoma, Wilm’s tumor) has been ascribed to AAS abuse in athletes. However, such reports have to be interpreted with some reservations. Diagnostics The use of AAS in sports is prohibited by doping regulations of the national and international sports federations. Since 1976, laboratory techniques to detect AAS are available. For decades, AAS are the most detected substances in doping controls in sports. In athletes, urine samples are obtained for analysis of doping substances, including AAS, by specialized laboratories that are accredited by the International Olympic Committee. Athletes who test positive on AAS will be punished by the sports federations. References 1. 2. 3. 4. 5. 6. Casavant MJ, Blake K et al (2007) Consequences of use of anabolic androgenic steroids. Pediatr Clin North Am 54(4):677–690, x Friedl K (2000) Effect of anabolic steroid use on body composition and physical performance. In: Yesalis C (ed) Anabolic steroids in sport and exercise, vol 2. Human Kinetics, Champaign, pp 139–174 Hall RC, Hall RC (2005) Abuse of supraphysiologic doses of anabolic steroids. South Med J 98(5):550–555 Hartgens F, Kuipers H (2004) Effects of androgenic-anabolic steroids in athletes. Sports Med 34(8):513–554 Kutscher EC, Lund BC et al (2002) Anabolic steroids: a review for the clinician. Sports Med 32(5):285–296 Van Amsterdam J, Opperhuizen A, Hartgens F (2010) Adverse health effects of anabolic androgenic steroids. Reg Pharmacol Toxicol 57:117–123 Anaerobic Metabolism Anaerobic Activity Anaerobic activity is a more intense form of muscular activity, where the cardiorespiratory system is unable to supply sufficient oxygen to meet metabolic demand, and there is a significant accumulation of lactate. Anaerobic activity is fuelled only by carbohydrate, and is rapidly fatiguing. Anaerobic Energy Expenditure Cellular energy demands that are met by anaerobic metabolism: glycolysis/glycogenolysis and stored ATP/CP. Anaerobic Glycolysis The catabolism of glucose or glycogen to lactic acid. Anaerobic Metabolism JAMES R. MCDONALD, L. BRUCE GLADDEN Department of Kinesiology, Auburn University, Auburn, AL, USA Synonyms Fermentation; Glycolysis; Phosphagen system Definition “▶ Anaerobic metabolism” is the production of adenosine triphosphate (ATP) through energy pathways that do not require oxygen. From early in the twentieth century, anaerobic metabolism implied pathways of energy metabolism that were activated due to a lack of O2 (dysoxia) [1]. However, it is now clear that the more common condition for faster rates of anaerobic ATP production is simply increased exercise intensity. In other words, neither a complete absence of O2 (anoxia) nor a relative lack of O2 (hypoxia) is a prerequisite for the recruitment of anaerobic pathways, and in fact, these pathways are routinely stimulated, both at the onset of exercise in the transition from rest to mild-to-moderate activity and during high-intensity exercise as more Type II muscle fibers are recruited [2]. A Basic Mechanisms What are the anaerobic reactions? The starting point is ATP hydrolysis: ATPþH2 O >>>>>>>>> ADP þ Pi þ Energy where ADP is adenosine diphosphate and Pi is inorganic phosphate. ATP is of course the universal supplier of energy, the “energy currency” of the cell, i.e., the chemical form that is required for most energy-requiring processes in the body. Foods are ingested and metabolized with a significant portion of the energy release being captured in the form of ATP. In exercise metabolism, the major energy-requiring processes in skeletal muscle are (1) crossbridge cycling to produce force and movement with the catalytic enzyme being myosin ATPase, (2) resequestration of Ca2+ into the sarcoplasmic reticulum powered by Ca2+-ATPase, and (3) restoration of the membrane potential via the Na+-K+-ATPase pump [4]. Although ATP is the required energy form, it is stored only in small quantities within the skeletal muscle [3, 5], only enough for a few seconds (s) of all-out sprinting. Thus, ATP must be replenished rapidly during exercise, or muscle contraction will stop. The pathways to replenish ATP typically keep levels at 70% or more of the resting concentration, and rarely if ever does the ATP concentration decline below 50% of the resting value [2]. Despite these relatively small changes in ATP concentration, cellular stores of ATP are considered part of the “immediate” anaerobic system because they are the first energy source used at the onset of exercise. These stores are replenished by (1) other components of the ▶ immediate energy system, (2) the glycolytic system, and (3) the oxidative system. All of these systems are stimulated at the onset of exercise, but the immediate and glycolytic systems have much, much faster response times. The major reaction of the immediate system involves phosphocreatine (PC): PC þ ADP <<<<<>>>>> ATP þ C ðcreatineÞ This reaction is catalyzed by creatine kinase and is so rapid and effective at resupplying ATP that it took nearly 35 years from the identification of ATP and PC until Cain and Davies in 1962 directly demonstrated (by poisoning the creatine kinase reaction) that ATP was the required energy form for muscle contractions [1]. Energy from the ATP and PC stores is delivered, as the name of the system implies, immediately with the start of exercise/muscle contraction. Experimental evidence shows that PC concentration declines by several mM in the first 10 s of heavy exercise with a continued rapid decline to approximately 30 s when PC is below 50% of its resting value, and continues to be 69 A A Anaerobic Metabolism depleted by as much as 80% or more as exercise is prolonged. The creatine kinase reaction reverses when there is an abundance of ATP as occurs in recovery [4]. Also part of the immediate energy system and triggered by intense exercise is the reaction catalyzed by adenylate kinase, sometimes referred to as myokinase in skeletal muscle: End Exercise Glycolytic 1.5 Oxidative 1 • ADP þ ADP <<<<<>>>>> ATP þ AMP Immediate 2 VO2 (L • min-1) 70 This reaction provides another route for replenishment of ATP, and reduces the concentration of ADP. This is arguably important for maintaining a higher ATP/ADP ratio which helps to maintain a high energy of hydrolysis for ATP breakdown [4]. While the immediate system appears to become fully active within the first 1–2 s after the onset of exercise, ▶ glycolysis, the second anaerobic system, is hypothesized to reach its maximum rate within about 7 s after exercise onset and then become the predominant system for ATP production as all-out exercise continues beyond 10 s [2]. Glycolysis continues to be the major producer of ATP until the aerobic system, ▶ oxidative phosphorylation, takes precedence in activities of longer duration. This has been generally considered to occur at 120 s of exercise but newer evidence has led to a downward revision to approximately 75 s [2]. Glycolysis, the second major anaerobic energy system, begins with glucose or glycogen and then through a series of enzymatic steps, produces two molecules of ATP and two molecules of pyruvate. Pyruvate is rapidly converted to lactate in a reaction catalyzed by lactate dehydrogenase (LDH), the enzyme having the highest activity of any enzyme in the glycolytic pathway. Due to this high activity, the LDH reaction is near-equilibrium, a condition in which the reaction is heavily in the direction of lactate such that lactate concentration is typically 10–200 times greater than pyruvate concentration [2]. Accordingly, lactate can correctly be considered the normal end product of glycolysis, regardless of whether or not lactate is increasing in concentration. At exercise intensities below 100% of _ 2max ), most of the lactate is maximal O2 uptake (VO reconverted to pyruvate in locations near mitochondria where the pyruvate enters the mitochondrial matrix to be fully oxidized through the pyruvate dehydrogenase reaction and the reactions of the Krebs cycle. The starting fuels for glycolysis are either glucose or glycogen (via glycogenolysis), but during intense exercise, glycogen becomes the sole fuel source. This is fortuitous given that the net ATP gain from glycogen to lactate is 3 as compared to only 2 ATP when glucose is the fuel. _ 2 ) response Figure 1 illustrates the oxygen uptake (VO to a submaximal exercise task and clearly shows that all 0.5 EPOC Rest 0 0 Begin Exercise 4 8 12 16 20 Time (min) _ 2 for 6 min of submaximal Anaerobic Metabolism. Fig. 1 VO exercise followed by 15 min of recovery. Oxidative metabolism _ 2 on-kinetics curve. is indicated by the area under the VO Glycolytic metabolism is indicated by the stippled area. The clear area above the glycolytic area, bounded by the steady state VO2 (min 4–6) at the top and the start of exercise on the left, is the immediate energy system contribution (primarily PC breakdown). The sum of the glycolytic and immediate areas is the O2 deficit. In recovery (which begins at min 6), the VO2 above the pre-exercise resting baseline is the O2 debt, or EPOC (excess postexercise oxygen consumption). See text for additional discussion three of the energy systems are activated at exercise onset, but that the oxidative system is slowest to reach its full _ 2 on-kinetics describe the oxiexpression (2–3 min). VO dative response and also reveal that there is an ▶ O2 deficit in terms of energy equivalents in the early phase of exercise. The oxidative energy equivalents for this deficit are provided by the rapidly activated immediate (primarily _ 2 PC) and glycolytic energy systems. In recovery, the VO remains elevated above the pre-exercise level for a considerable period of time, producing what is known as an ▶ O2 debt or ▶ EPOC (excess postexercise O2 consumption). There is a general relationship between the EPOC and O2 deficit mainly because the PC that is broken down at exercise onset is resynthesized early in recovery at an added energy cost above the pre-exercise baseline. However, the contribution of lactate removal to the EPOC is variable, and typically small because most of the lactate accumulated during early exercise is oxidized as a fuel during recovery, a process that does not require extra O2 consumption [2]. Much of the EPOC (other than that due to PC resynthesis) is caused by elevated cardiovascular Anaerobic Power, Test of and respiratory activity, elevated hormones (particularly epinephrine), elevated body temperature, and fatty acid recycling with an additional small amount for refilling blood and muscle O2 stores. Rapid accumulation of lactate in muscle and blood with an accompanying decrease in pH is the hallmark of accelerated glycolysis. At normal body pH values (6.4–7.4) both pyruvic acid and lactic acid are nearly completely dissociated into a proton (H+) and a pyruvate or lactate anion, respectively. Lactate movement across cell membranes is facilitated by a family of carrier proteins called monocarboxylate transporters (MCTs) of which MCT1, MCT2, and MCT4 appear to be the major isoforms [1, 2]. Currently, there is overwhelming evidence that lactate is not simply a dead-end waste product, but is instead a highly mobile fuel that circulates through the body from lactate-producing tissues to lactate-utilizing tissues [1, 2]. Resting and mild to moderately exercising muscles (particularly oxidative muscle fibers), the heart, and the brain can use lactate as a fuel. The liver and kidney are primary sites for lactate uptake and conversion to glucose (gluconeogenesis). This distribution of lactate and its utilization by most tissues of the body is known as the ▶ cell-to-cell lactate shuttle, a concept that was formulated by George Brooks at the University of California, Berkeley [2]. A mainly on the glycolytic system and thus create high lactate levels include running and swimming events between 30 s and 2 min. Training usually relies on high-intensity efforts of the same length or slightly longer than the target event with shorter recovery periods. Recovery between intense exercises as in interval training ranges from twice the exercise time, a 1:2 ratio, to half the time it took to complete the exercise, a 1:0.5 ratio. References 1. 2. 3. 4. 5. Brooks GA, Gladden LB (2003) The metabolic systems: anaerobic metabolism (glycolytic and phosphagen). In: Tipton CM (ed) Exercise physiology: people and ideas. Oxford University Press, New York, pp 322–360 Gladden LB (2003) Lactate metabolism during exercise. In: Poortmans JR (ed) Principles of exercise biochemistry, 3rd edn. Karger, Basel, pp 322–360 Gollnick PD (1973) Biochemical adaptations to exercise: anaerobic metabolism. Exerc Sport Sci Rev 1:1–44 Houston ME (2006) Biochemistry primer for exercise science. Human Kinetics, Champaign Kraemer WJ (1994) General adaptations to resistance and endurance training programs. In: Baechle TR (ed) Essentials of strength training and conditioning. Human Kinetics, Champaign, pp 127–150 Anaerobic Power, Test of Exercise Interventions The anaerobic systems are involved at the onset of all types of exercise, but are especially prevalent in high-intensity exercise. Therefore, these systems are relevant in short bursts of speed and power that are typically found in sports like football, weightlifting, gymnastics, and basketball, as well as in sprinting, track, swimming, and cycling. Exercises for training the phosphagen and glycolytic systems are generally intense, of short duration, and involve more time in recovery than in the exercise itself [5]. PC concentration in muscles can be elevated by exercise training and creatine supplementation. Exercises to improve this system focus on repeated short sprint activity (e.g., 10 s) with comparatively much longer recovery intervals. “Creatine loading” to elevate resting PC levels elicits improvement in exercise performance in shortduration events and faster gains in muscle mass and strength with resistance training [4]. However, results with highly trained athletes, in particular elite sprint athletes, are sparse and less clear, failing to show clear improvements in performance with creatine loading. Training the glycolytic system focuses on improving the body’s ability to buffer or tolerate high lactate levels and the accompanying acidosis [5]. Events that rely OMRI INBAR Department of Life Sciences, Zinman College Wingate Institute, Netania, Israel Synonyms Short-term power testing Definition Anaerobic power testing is the evaluation of the human capacity to perform short-term work at the highest possible rate. Relevant work durations range from a few seconds to about 1 min. Description Historical Perspective Quantification of anaerobic power and fitness did not start taking place until the mid-1960s – nearly a quarter of a century since aerobic power testing began. Despite its role as a major component of physical performance capacity, anaerobic fitness testing is still rarely included in standard fitness evaluations. 71 A 72 A Anaerobic Power, Test of Anaerobic Metabolism Higher organisms use anaerobic metabolism for two primary reasons: (a) to bridge temporary gaps between the slow-responding aerobic metabolism and the immediate energy demands at the onset of physical activity and (b) to supplement aerobic metabolism in attaining short-term power output exceeding that which can be attained by aerobic metabolism alone. There are two distinct kinds of anaerobic energy sources: (a) Phospholytic energy, derived from tapping existing phosphagen (ATP & PCr) stores. While its response to exercise demands and the rate of its release (power) are extremely high, the total energy available from phospholysis is greatly limited by phosphagen stores’ size. (b) Glycolytic energy, which produces new ATP and replenishes phosphagen stores via glycolysis. The energy available from this source depends on exercise mode and intensity and on hydrogen ion accumulation, but is many times greater than phospholytic energy. Maximal glycolytic power output is intermediate between maximal aerobic power and peak phospholytic power outputs. Functional Attributes of Anaerobic Power By its very nature, anaerobic power production is largely independent of circulation and oxygen supply and, therefore, is mostly determined by the metabolic and functional (e.g., neuro-motor control, motor-unit composition) characteristics of the involved muscles. That is, unlike aerobic power, which to a large extent depends on central cardiopulmonary factors, anaerobic power is a local/ peripheral phenomenon. This would mean, for example, that training the anaerobic power of a given muscle or muscle group cannot be expected to affect other muscles. While aerobic power is directly related to oxygen consumption, there is no comparable variable by which the anaerobic component of a given exercise can be teased out from the overall power output. Thus, anaerobic power must be evaluated by physical exercise that is sufficiently short so as to limit aerobic contribution and ensure anaerobic dominance of the test. General Considerations in Anaerobic Testing General anaerobic fitness. Being muscle-specific, anaerobic performance capacity cannot be whole-body tested. However, in the general untrained or non-specifically trained population, there is a good correlation between the anaerobic fitness of major muscle groups (e.g., legs) and the rest of the body’s musculature. General anaerobic fitness, therefore, is typically tested in leg exercise (mainly cycling). Upper-/lower-body specificity. When lower-body (leg) ergometry is impossible (e.g., in paraplegics, leg amputees), or when specific training is involved (e.g., kayaking vs. cycling, or swimming vs. running), upperbody (arm) ergometry can be performed to best represent the individual’s anaerobic fitness. Specificity of test modality. Anaerobic training effects are specific not only to the involved muscle group but to the specific nature and modality of training. Thus, compared to a runner, a cyclist is expected to have a priori advantage in cycle ergometry although nearly identical muscle groups are involved. Test duration. Determines the proportional contribution of aerobic vs. anaerobic metabolism to the measured work and power output and the relative involvement of anaerobic endurance in the overall performance. Thus, the longer the test, the higher the aerobic contribution and the involvement of anaerobic endurance (enduring increasing acidosis). Phospholytic power. Can only be estimated by 5–10-s all-out exertions or from the initial segments of like durations in longer all-out exertions. Glycolytic power. Fully activated only several seconds into a strenuous exertion, it has a longer effective span than phospholytic power. It is therefore best estimated by maximal exertions of 20–40 s. Shorter durations would be too phospholytic while longer ones too aerobic. Anaerobic capacity. The kinetics of the phospholytic, glycolytic, and aerobic metabolic pathways do not allow for a single exertion to provide a work- or power-output value representative of the whole-body capacity for anaerobic energy production. This is reflected by the highest attainable lactate concentration, typically following 2–4 min of maximal whole-body (e.g., rowing, crosscountry skiing) or lower-body (e.g., running, cycling) exercise. Lactate, however, is only a rough indicator since lactate is unevenly distributed among the various body compartments and is already actively metabolized during the exertion. The accepted, more valid measure of anaerobic capacity is the maximal oxygen debt (excess postexercise oxygen consumption) following such an exertion. It should be re-emphasized that in athletes a meaningful test must involve their specific mode of exercise. Subject population. Anaerobic testing is extremely intense and for reasons of both safety and relevance it should not be administered to the old, the frail, or the cardiovascularly impaired. Application Various tests have been used since the mid-1960s for evaluating anaerobic fitness. Some of the most common and significant are described in Table 1. The nature of anaerobic fitness dictates that no single test can provide the best possible evaluation of all its components. Anaerobic Power, Test of A Anaerobic Power, Test of. Table 1 Comparison of common laboratory tests of anaerobic fitness Test Ergometer Duration Measures Motorized treadmill test (MTT) Treadmill 80–120 s Anaerobic r = 0.76–0.84 capacity Low (high aerobic contribution) Nonmotorized treadmill test (NMT) Passive, nonmotorized treadmill 30 s Isokinetic monoarticular test (IMT) Isokinetic 30 s dynamometer Wingate anaerobic test (WAnT) Cycleergometer 30 s Reliability Validity A Comments GP, PP r = 0.82 – PP, 0.88 – GP Aerobic contribution not known GP, PP, FI No data r = 0.94 for GP. Low r’s for PP, Expensive FI, and sprinting capacity equipment GP, PP, FI r = 0.87–0.98 Non-standardized computation of power Isokinetic contractions are atypical of normal exercise tasks Difficult to modify for children High with many anaerobictype performances and physiologic measures Most validated and researched test Simple to perform Applicable to both lower and upper extremities Forcevelocity cycling test (FVT) Cycleergometer Isokinetic cycling test Cycleergometer Accumulated Cycleoxygen ergometer or deficit test treadmill (AOD) 4–6 sprints, 5–10 s each Mainly PP 6s PP only 2–4 min 11.9% testNo data retest CV for PP 3.5% for adolescents Time consuming (40–60 min) 5.4% test-retest Isokinetic contractions are CV for GP atypical of normal exercise tasks Time consuming Anaerobic 0.95–0.98 capacity interclass correlations for time to exhaustion Low correlations with WAnT, but good correspondence with several anaerobic field performances Motivation is likely compromised with duration Expensive equipment Time consuming (lengthy pretests to establish VO2-power relationships) Exercise mode specific Assumed linearity of VO2-power relationship below and above AnT PP phopholytic/peak power, GP glycolytic power, FI fatigue index (WAnT), CV coefficient of variation, AnT anaerobic threshold Particular needs may be met by different tests. Also, anaerobic tests were typically developed on healthy and active young adult populations. Extending the use of such tests to children and other atypical populations may be unwarranted. Since the mid-1970s, the Wingate Anaerobic Test (WAnT) has been the most researched, validated, reliability-verified, and widely used test on varied populations, and it evaluates three distinct anaerobic fitness 73 components [1, 2]. The WAnT is the universally accepted test of choice and will be described in the following sections. The WAnT Ergometers. While electromagnetically braked cycleergometers have been a boon to general ergometry, their loading characteristics in WAnT ergometry have not yet 74 A Anaerobic Power, Test of been reconciled with those of their mechanically braked counterparts. Only the latter will be referred to here. Upperbody ergometry is facilitated by modified cycle-ergometers or dedicated arm-ergometers with identical test protocols [1]. Setup. Seat height is individually adjusted according to accepted standards, with toe-clips or the equivalent used for securing feet to pedals. A forward leaning posture is attained by proper handlebar adjustments. In arm ergometry the crank axis of rotation should be set at shoulder height. In both leg and arm ergometry, both ergometers and subjects must be secured in a way that prevents undue motion during the test. Resistance load. Determined according to body mass and composition, age, and fitness level, as recommended in Table 2. Warm-up. Five to ten minutes of mild to moderate intensity pedalling interspersed in its latter part by three 4- to 7-s all-out sprints against the gradually applied test load; a rest period of 2–3 min follows. Load application. (a) Upon the start command, the subject accelerates the unloaded flywheel, as fast as possible, against its inertial resistance. (b) Following ~3 s, as pedal revolution rate starts to plateau the predetermined load is applied. (c) The actual test begins (monitoring of time and pedal revolutions). The subject continues to pedal, as fast as possible (no pacing), for the entire 30-s duration of the test. Verbal encouragement is continuously given to facilitate maximal effort. Results. Figure 1 illustrates a typical WAnT output and its three derived variables: (a) Mean Power (MP). Mean power output throughout the test’s 30-s duration. It is the WAnT’s primary variable (for which the test was optimized) and largely represents glycolytic power. It is calculated as: MPðWattÞ ¼ MLoad  g  D  n30 =30 where MLoad = resistance (friction) load mass (kg) Anaerobic Power, Test of. Table 2 Recommended resistance loading Units: Children 1 ● J·kg BW·rev 1a ● g·kg 1BW (Fleisch) ● g·kg 1BW (Monark) Leg ergometry Pre-pubescent ♂ ♀ Arm ergometry ♂ ♀ Pubescent Adolescents and young adults (up to 30 year) 3.92 4.41 4.90 40 45 50 66.7 75 83.3 3.92 4.41 4.70 40 45 48 66.7 75 80 2.65 2.94 3.43 27 30 35 45 50 58.3 2.65 2.65 2.65 27 27 27 45 45 45 “Reference” subject Lean to normal weight, sedentary to mildly active Age adjustment Reduce resistance by 5% for every 10 years beyond 30 % Fat adjustment Reduce resistance by 10% for every 10% rise in fat percentage above 15% Fitness adjustment (anaerobic fitness) - Reduce resistance by up to 10% for particularly unfit subjects - Raise resistance by 10% for active, anaerobically fit subjects - Raise resistance by 20% for elite anaerobically trained subjects Electromagnetically braked WAnT ergometers set their own resistance and are not adjustable Universal loading unit, independent of specific design of the particular mechanically braked ergometer a Anaerobic Power, Test of A 75 A Pmax (PP) Power Fatigue Pmin Mean Power (MP) = Area under the curve Fatigue Index (FI) = (Pmax – Pmin)/Pmax x 100 0 5 10 15 Time, s 20 25 30 Anaerobic Power, Test of. Fig. 1 WAnT schematics g = 9.81 m/s2 (gravitational acceleration) D = flywheel circumference (m) [6 and 10 m for Monark and Fleisch, resp.] n30 = 30-s pedal revolutions count (b) Peak Power (PP). The mean of the highest 5-s power output (typically, the first 5 s). Largely represents phospholytic power. PPðWattÞ ¼ MLoad  g  D  nmax =5 where nmax = highest 5-s pedal revolutions count (c) Fatigue Index (FI). The percentage drop in power output from PP to Pmin (see Fig. 1). FI is typically low in endurance-athletes and high in power-athletes. Recommended Resistance Loading Maximal power is the largest attainable product of force (resistance) and velocity (/ pedal RPM). Since the two components are conversely interrelated, maximal power occurs at the mid-portions of their attainable ranges. Optimal load, therefore, is one that enables maximal power output in most cases of a given subject population. Compared with the normal stature and fitness, subjects of higher relative muscle mass or fitness require higher loads while overweight or under-fit subjects require reduced loads [1, 3]. The WAnT is optimized to maximize MP. Table 2 provides the recommended loads for standard child and adult populations of both sexes with adjustments for body composition, age, and fitness level. The use of optimal braking torque based on total body mass assumes that people have a similar relationship between muscle mass and total body mass. While this may be true for the general healthy population, it will be untrue for people with marked obesity, malnourished, muscle atrophy, muscle dystrophy, etc. Further research is required to assess the optimal resistance for such groups. Limitations/Special Considerations [4] While the WAnT has been widely used and is the test of choice since the early 1980s, variability in application has affected the universality of results. This must be accounted for in comparing data from different sources or using performance norms (see below). This variability stems from the following: 1. Use of ergometers of different designs, resistance characteristics, and consequent results. Most notable is the use of mechanically braked cycle-ergometers (on which the WAnT was developed and validated) as well as electromagnetically braked ergometers. 2. Use of different application protocols. Most notable are differences in the timing of load application (test onset) and warm-up characteristics. 3. Use of non-optimal loading. 76 A Anaerobic Threshold Anaerobic Power, Test of. Table 3 Predictive equations for typical PP/kg and MP/kg during the WAnT Limb Gender Variable Leg ergometry ♂ MP/kg ♀ Arm ergometry ♂ 4.378 + 0.263  age – 0.005  age2 N R2 180 0.884 45 0.650 2 PP/kg 4.738 + 0.349  age – 0.006  age MP/kg 4.476 + 0.099  age – 0.002  age2 PP/kg 2.568 + 0.453  age – 0.008  age2 2 MP/kg 1.07 + 0.613  age – 0.016  age PP/kg 0.44 + 0.864  age – 0.023  age2 0.846 0.972 130 0.994 0.997 No sufficient data are available for females’ arms and for the fatigue index 4. Use of a single crank length (170 mm) for adults and children of all sizes. 5. Non-standardized saddle height. 6. Use of different algorithms for WAnT data derivation (e.g., Monark and Lode use different algorithms, both deviating from the original). 7. Computerization and high-resolution revolution counting have increased data accuracy and reliability (PP and FI in particular). 8. WAnT’s original algorithm did not account for kinetic energy gained in acceleration, prior to load application, resulting in somewhat inflated power values – PP in particular. Some later algorithms (e.g., Monark and Lode) have corrected this. Norms Norms are essential for the evaluation and the establishment of performance criteria. The following normative formulae are the result of a judicious compilation of published data from several sources. Based on these results, stepwise regression analysis was performed to create predictive equations and to determine the accuracy with which peak and mean power, for a standard 30-s WAnT, could be predicted (see Table 3). It should be emphasized, however, that the database is limited in size, particularly in some categories (mainly in females). This, in conjunction with the limitations listed above, places the predicted norms in a tentative rather than authoritative category. Also, children’s performance data during maturation is best evaluated relative to maturational rather than chronological age. The former, however, is often unavailable and the norms are consequently age based [2, 5]. Nonetheless, the use of such simple predictive equations allow the calculation of normal values for females and males and for arm and leg WAnT performance of a wide range of ages, for comparison of data to published norms. References 1. 2. 3. 4. 5. Inbar O, Bar-Or O, Skinner JS (1996) The Wingate anaerobic test. Human Kinetics, Champaign Maud PJ, Schultz BB (1989) Norms for the Wingate anaerobic test with comparison to another similar test. Res Q Exerc Sport 60:144–151 Dotan R, Bar-Or O (1983) Load optimization for the Wingate anaerobic test. Eur J Appl Physiol 51:409–417 Dotan R (2006) The Wingate anaerobic test’s past and future and the compatibility of mechanically versus electro-magnetically braked cycle-ergometers. Eur J Appl Physiol 98:113–116 Inbar O, Bar-Or O (1986) Anaerobic characteristics in male children and adolescents. Med Sci Sports Exerc 18:264–269 Anaerobic Threshold KARLMAN WASSERMAN Respiratory and Critical Care Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA Synonyms Individual anaerobic threshold (IAT); Lactate threshold; Lactic acidosis threshold Definition The anaerobic threshold (AT) is the exercise O2 uptake (V_ o2 ) below which work is sustained totally aerobically, without an increase in arterial blood lactate, and that level of exercise above which ▶ anaerobic glycolysis supplements ▶ aerobic glycolysis, lactate accumulates, lactic acidosis develops, and the lactate/pyruvate ratio increases (the Pasteur effect). Below the AT, the transport of O2 to the muscles is sufficient to regenerate the adenosine triphosphate (ATP) to power the muscles, aerobically (mitochondrial Anaerobic Threshold respiration). Above the AT, the muscle capillary PO2 falls to a critically low level, so that if exercise level increases, anaerobic glycolysis increases, and lactate accumulates in the systemic circulation (Fig. 1) [1]. The AT could be determined by measuring the threshold of arterial lactate increase, bicarbonate decrease, or the onset of increased CO2 output from HCO3 buffering of lactic acid (gas exchange) [2, 3]. Description The AT was developed as a measure of cardiovascular function, i.e., the maximal rate at which the circulation is able to supply O2 for sustaining a given form of exercise, aerobically. Above the AT, anaerobic glycolysis and lactate accumulation are added to the aerobic bioenergetic sources of ATP during exercise [4]. Differences Between Aerobic and Anaerobic Glycolysis Glucose (glycogen) is the primary substrate which undergoes catabolism to regenerate ATP for exercise A (Fig. 2) [6]. There is an oxidative step in glycolysis in which coenzyme nicotinamide adenine dinucleotide (NAD+) accepts two protons, converting it to the reduced form (NADH + H+). To continue the breakdown of glucose to pyruvate, and subsequent decarboxylation to combine with co-enzyme-A for acetate’s entry into the mitochondrial tricarboxylic acid cycle and electron transport chain complex, the reduced cytosolic NADH + H+ must be reoxidized back to NAD+. For this, NADH + H+ must be reoxidized either by the mitochondrial membrane shuttle, aerobically (Fig. 2, pathway A) or, anaerobically by pyruvate (Fig. 2, pathway B). Pathway A consists of dihydroxy acetone phosphate which reoxidizes NADH + H+ back to NAD+. The resulting saturated molecule is glycerol phosphate, which is apparently readily permeable to the outer mitochondrial membrane. In the mitochondria, glycerol phosphate is reoxidized by flavine adenine dinucleotide (FAD). The reduced FADH + H+ is reoxidized back to FAD by the electron transport chain, with the production of two ATP [6]. If the O2 supply to the mitochondria were insufficient to reoxidize 14 12 LAC (mEq/L) :Heart disease n=5 :Sedentary n=4 :Active n=20 10 8 6 4 2 Vo2 (L/min) 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Anaerobic Threshold. Fig. 1 Pattern of increase in arterial lactate in active and sedentary healthy subjects and patients with _ 2 ) during exercise. Arterial lactate (LAC) concentration rises from approximately heart disease as a function of oxygen uptake (Vo the same resting value to peak concentration at maximal exercise in each of the three groups. The fitter the subject for aerobic _ 2 before lactate starts to increase above resting levels. (Modified from [1]) work, the higher the Vo 77 A A Anaerobic Threshold BLOOD Qm·CaO2 O2 O2 O2 O2 O2 Qm·CvO2 O2 CO2 O2 GLYCOGEN GLUCOSE CYTOSOL EMBDEN-MEYERHOF PATHWAY NAD+ 3 ATP NADH + H+ A = Aerobic glycolysis B = Anaerobic glycolysis ALANINE A PYRUVATE B LACTATE FFA PROTON “SHUTTLE” PYRUVATE DEHYDROGENASE MITOCHONDRIAL “MEMBRANE” CO2 FAD MITOCHONDRION 78 FADH2 CO2 ACETYLCOA NAD+ NADH + H+ TCA CO2 ATP ATP ATP ATP ELECTRON TRANSPORT ½ O2 H2O FAD FADH2 Anaerobic Threshold. Fig. 2 The major biochemical pathways for production of ATP. The transfer of H+ and electrons to O2 by the mitochondrial electron transport chain and the “shuttle” of protons from the cytosol to the mitochondrion (Pathway A) are the essential components of aerobic glycolysis. This allows the efficient use of carbohydrate substrate in regenerating ATP to replace that consumed by muscle contraction. Also illustrated is the important O2 flow from the blood to the mitochondrion, without which the aerobic energy generating mechanisms within the mitochondrion would come to a halt. At the sites of inadequate O2 flow to mitochondria, Pathway B serves to reoxidize NADH + H+ to NAD+ with a net increase in lactic acid production (lactate accumulation). Lactate will increase relative to pyruvate as NADH + H+/NAD+ increases in the cytosol [5] the mitochondrial membrane proton shuttle (glycerol-3 phosphate) back to its unsaturated form (dihydroxy acetone phosphate), pyruvate reoxidizes cytosolic NADH + H+ back to NAD+. By accepting the two protons, pyruvate becomes lactate. Lactate accumulation is an end reaction of anaerobiosis. It is reversed back to pyruvate when sufficient O2 is available to normalize the cytosolic redox state (NADH + H+/NAD+) [1, 7]. As the cytosolic redox state moves to the reduced state, anaerobic glycolysis accelerates, and the arterial lactate/pyruvate ratio increases (Fig. 3) [7]. The increased lactate/pyruvate ratio reverses at the start of recovery from exercise [7]. Lactate Accumulates During Exercise at _ 2 a Threshold Vo Careful repeated studies of arterial lactate relative to increasing V_ o2 reveal that lactate concentration increases Anaerobic Threshold 1.0 1.0 0.0 − log [La−] [La ] −0.5 0.0 − [Pyr ] −1.0 0.0 −1.0 −1.0 0.0 1.0 log VO2 Anaerobic Threshold. Fig. 3 Arterial log lactate [La–], log pyruvate [Pyr–], and log lactate/pyruvate (L/P) ratio plotted against log _ 2 and pyruvate-Vo _ 2 relationships allows easy detection of the lactate and pyruvate _ 2 . The log-log transform of the lactate-Vo Vo _ 2 than the lactate inflection point. Because the pre-threshold inflection points. The pyruvate inflection point is at a higher Vo pyruvate slope is the same as the lactate slope, the L/P ratio does not increase until after the lactate inflection point [7] at a threshold V_ o2 [7, 8]. It does not increase as a continuum or exponential function [8], as some authors had speculated. The ▶ lactate threshold increases with fitness and decreases with cardiovascular diseases affecting O2 transport [1]. Lactate accumulates during exercise as an anion, its negative charge being balanced by H+. Thus it requires buffering to maintain arterial H+ homeostasis and avoid physiologically important changes in arterial blood pH. This is done by bicarbonate (HCO3 ), a ▶ volatile buffer. See equation below: pHa ¼ pK1 þ ½Naþ HCO3 Š=½H2 CO3 Š ¼ pK2 þ½Naþ Lac Š=½Hþ Lac Š ¼ pK3 þ½Naþ Org Š=Hþ Org Š Na+Org represents all salts of weak acids capable of serving as acid buffers and are converted to acids (H+Org ) when buffering. These nonvolatile buffers can be activated to buffer H+ only when the pHa changes, sufficiently. However, pH changes of the aqueous fluids of the body are defended, first and foremost, by the HCO3 buffer. Theoretically and experimentally, HCO3 is the first buffer used to regulate cell and blood H+ because the resulting acid, H2CO3, dissociates into CO2 and H2O. The CO2 is eliminated by the lungs, while the H2O is neutral. As long as HCO3 buffer is available, nonvolatile buffers could not serve as H+ buffers because the H+ concentration increases little. To buffer H+, the nonvolatile buffer would need to be exposed to a significantly reduced pH and be quantitatively significant relative to HCO3 . 79 A L /P log [Pyr− ] log L /P 1.5 0.5 A Buffering of the Accumulating Lactate Lactate is the end product of anaerobic glycolysis. Its pK equals 3.8. Therefore, over 99% of the lactate increase during exercise is dissociated, functioning as an anion, its negative charge balanced by H+ at the pH of blood and cell water. The H2CO3 generated during acid buffering dissociates into CO2 and H2O. The CO2 is eliminated by the lungs, leaving behind neutral water. Thus the lungs regulate H+ of metabolic as well as respiratory origin. Bicarbonate and Lactate Thresholds Bicarbonate decrease approximates lactate increase, millimol for millimol, after the first minute of exercise [3, 9, 10]. Figure 4 shows the simultaneous arterial lactate and HCO3 concentrations as related to time, while cycling at three different work intensities [10]. Figure 5 shows that virtually all of the lactic acid buffering is by HCO3 , although the 1:1 relationship is displaced from the origin by about 0.5–1.0 millimol [9]. Beaver et al. showed that both the increase in lactate and decrease in bicarbonate have V_ o2 thresholds [3]. HCO3 decrease is delayed relative to lactate increase by about 0.5 millimol [3]. This delay in HCO3 decrease relative to lactate increase was consistent in three studies in which the stoichiometry of the buffering was determined [3, 9, 10]. The buffer of the lactic acid accumulated during the first minute of exercise is also HCO3 . However, it is new bicarbonate formed during exercise with the alkalinization of muscle after the start of exercise [11]. It corresponds to the splitting of phosphocreatine. The phosphocreatine is an anion, which on splitting becomes A Anaerobic Threshold 12 [La-] (mEq./L) 10 Very Heavy 8 6 Heavy 4 2 Moderate Moderate 24 [HCO -3] (mEq./L) 80 22 Heavy 20 18 16 very Heavy 14 5 10 15 20 30 25 TIME (min) 35 40 45 50 Anaerobic Threshold. Fig. 4 Arterial lactate increase and bicarbonate decrease with time for moderate, heavy, and very heavy exercise intensities for a normal subject. Bicarbonate changes in opposite direction to lactate and in a quantitatively similar manner. While the target exercise duration was 50 min for each work rate, the endurance time was reduced, the greater the lactate increase [5] a neutral molecule (zwitter ion). This results in an excess of muscle cell cations (K+), which is seen in the muscle venous blood as early as 5 s after the start of exercise (5 s sampling). The new anion balancing the K+ is HCO3 , generated from aerobic metabolism. Within the first minute of exercise, K+ and HCO3 appear to increase in the muscle venous blood, stoichiometrically [11] with a transient increase in pH. In summary, all of the buffering of the increased lactate concentration during exercise could be accounted for by HCO3 buffer, taking into account the HCO3 formed during exercise. The Critical Capillary PO2 In studies on normal male subjects in whom femoral vein (FV) lactate was measured simultaneous with FV PO2, Stringer et al. [12] found that lactate did not increase until the end-capillary (FV) PO2 of the exercising muscle reached a minimum value (approximately 20 mmHg). The FV PO2 remained constant, at its minimum value from the AT to peak V_ o2 , despite increasing work rate. While FV PO2 did not decrease further above the lactate threshold, oxyhemoglobin saturation continued to decrease [12]. The decrease in oxyhemoglobin saturation, without a decrease in FV PO2, could be accounted for by the rightward shift in the oxyhemoglobin dissociation curve caused by the acidification of the capillary blood (Bohr effect) [13]. Koike et al. [14] studied the critical capillary (femoral venous, FV) PO2 during leg cycling exercise in ten patients with cardiovascular disease. Like the study of Stringer et al. on normal subjects, the FV lactate did not increase until the FV PO2 decreased to its minimal value, i.e., the critical capillary PO2. The gas exchange AToccurred soon after the critical capillary PO2 was reached. Thereafter, the FV PO2 during increasing work rate either remained constant (five patients) or reversed direction and increased (five Anaerobic Threshold Heavy Very Heavy Y = .998 (x) − 0.483 r = .904 Y = .951 (x) − 0.989 r = .968 a A A b Std HCO3- Decrease (mEq/L) 16 12 8 4 0 −2 −2 0 4 8 12 16 −2 0 4 8 12 16 Lactate Increase (mEq/L) Anaerobic Threshold. Fig. 5 Arterial standard (Std) HCO3– decrease as function of lactate increase from resting values for heavy and very heavy work intensities. The decrease in Std HCO3– is delayed by about 1 min, allowing lactate to increase by about ½ to 1 millimol/l of arterial blood plasma before HCO3– decreases from rest (see regression equations in figure). Changes are approximately equal and opposite (heavy, n = 181: slope = 0.998 (CI 0.92–1.06), intercept = 0.48 (CI 0.71 to 0.26); very heavy, n = 141: slope = 0.951 (CI 0.92–0.98), intercept = 0.99 (CI –1.12 to 0.78)) [9] patients). However, FV PO2 did not decrease further, despite increasing work rate and FV lactate [14]. Does the Anaerobic Threshold Demarcate the O2 Flow Insensitive and Sensitive Zones of Exercise Work Rate? The mechanisms and patterns of lactate increase during exercise were studied in humans, particularly as related to the O2 supply–O2 demand relationships during exercise [15]. Altering O2 transport was found to affect lactate increase and the AT [16]. Koike et al. [17] measured the effect of reducing blood O2 content without changing arterial PO2, by adding low concentrations of carbon monoxide to the inspired air. In this study, carboxyhemoglobin was increased to the 10% and 20% levels in each subject. Peak V_ o2 and AT decreased by approximately the same percent as the reduced O2 content of the blood. Additionally, V_ o2 was not affected below the subjects measured AT, demonstrating its insensitivity to blood O2 content. In contrast, the V_ o2 progressively decreased as work rate increased above the AT. The more reduced the arterial blood O2 content, the greater the reduction in V_ o2 . Thus V_ o2 is sensitive to O2 transport above the AT. 81 Clinical Use/Application Gas Exchange Methods for Measuring the Anaerobic (Lactate) Threshold The use of gas exchange to measure the AT evolved over the past 45 years, as added factors affecting exercise gas exchange were learned. Today and for the past 25 years, we rely primarily on the V-slope method for measuring the AT [2]. The lactic acid increase above the AT is immediately buffered by HCO3 , releasing quantitatively, 22.3 ml of CO2 for every millimol of lactic acid accumulating (Avogadro’s number) [18]. The following is a brief overview of how gas exchange measurements evolved to measure the AT (lactate or ▶ lactic acidosis threshold) by gas exchange. The Increase in Respiratory Exchange Ratio (R) The 1964 approach was to detect the increase in CO2 output (V_ CO2 ) from HCO3 buffering of accumulating lactic acid [4]. This was attempted by measuring the increase in the ratio V_ CO2 /V_ o2 or respiratory exchange ratio (R), breath by breath [4]. The hypothesis was that the rate of CO2 output would increase by 22.3 ml, 82 A Anaerobic Threshold quantitatively, for each millimol of lactate accumulating. This approach proved insensitive because the R generally increased during exercise without a lactic acidosis. The increase in R below the AT resulted from muscle substrate being heavily in favor of carbohydrate (glycogen) [19] compared to the energy substrate used by the body as a whole. Therefore, R usually increased during exercise even without developing a lactic acidosis. become >1.0. The rate of buffer CO2 produced depends on the rate of lactate accumulating, not the lactate concentration itself. Thus the increase in work rate should be sufficiently rapid to easily visualize the steepening of the V_ CO2 versus V_ o2 slope (about 12 min or less from rest to peak V_ o2 ). The V_ o2 at the intercept of the two slopes (below and above the steepening of CO2 output is the AT) correlates with the lactate and HCO3- thresholds [2, 3]. The Ventilatory Equivalent Method The Shortcut for Measuring the AT by the V-Slope Method This approach, described in 1973, took advantage of the disparity between the proportional increase in V_ E relative to V_ CO2 , at the onset of the buffering of the exercise lactic acidosis and the faster increase in V_ E relative to V_ o2 [20]. At the AT, V_ E/V_ o2 increased due to the stimulus of the extra CO2 released during HCO3 buffering, while V_ E/V_ co2 remained constant,(V_ E increasing proportionally to V_ co2 ). Thus PETO2 increased at the AT while PETCO2 remained constant for several minutes before it decreased in response to the acid drive [20]. The delay between the increase in V_ E/V_ CO2 relative to the increase in V_ E/V_ o2 is referred to as the isocapnic buffering period, because PaCO2 and PETCO2 remained constant during this interval. While this method was an improvement over the detection of an increase in R, particularly in normal subjects, it had limitations in some patient groups. It depended on the absence of physiological constraints on breathing, such as that due to severe airflow limitation or chest wall restriction (e.g., obesity). The V-Slope Method for Measuring the Anaerobic Threshold Recognizing the shortcomings of the earlier methods, Beaver et al. [2] developed a method for detecting the AT that depended only on the detection of the onset of the buffering of the lactic acidosis. This is an obligatory physical-chemical reaction that does not depend on the sensitivity of ventilatory chemoreceptors and the ventilatory response to the acid drive. Thus, it overcame the shortcomings of the prior methods. This method is called the V-slope method because it measures the volume of muscle CO2 produced as a function of the simultaneous volume of muscle O2 consumed on equal axes [2]. During exercise below the AT, V_ CO2 increases at about the same rate as, or slightly less than, the increase in V_ o2 because the muscle substrate is almost totally carbohydrate (respiratory quotient = 1.0). However, as soon as HCO3 in the cell starts to buffer the increase in lactic acid, V_ CO2 increases relative to V_ o2 . The rate of V_ CO2 increase must be 22.3 ml/mmol lactate buffered by HCO3 . This causes the slope of V_ CO2 versus V_ o2 to abruptly increase and Measuring the AT by the V-slope principle does not require complex calculations. A clear plastic 45o right triangle suffices to line up on the points of V_ CO2 vs V_ o2 below the AT. The points falling, systematically, along the edge or slightly below the 45o slope of the triangle indicate the rate of CO2 molecules produced relative to the number of O2 molecules consumed. (Hyperventilation with respect to CO2 does not occur until later, if it occurs.) At some point on this plot, the slope abruptly steepens, becoming >1.0 (>45o). The V_ o2 at the intercept of the two slopes can be read from a perpendicular line to the X-axis. This is the AT. The V-slope method depends only on the physical chemistry of buffering. The development of the V-slope method makes it possible to measure the AT in all normal subjects and almost all patients, regardless of the pathophysiology. The exceptions might be in patients with severe physical limitations, preventing the patient from reaching their AT, and patients with severe peripheral arterial disease so that the AT cannot be visualized by V-slope. However, this clinical problem can be quantified by other gas exchange methods during exercise. Physiological Significance and Clinical Applications of the AT A number of important physiological responses to exercise are altered above the AT [21]. Many of these have been described [5]. Among them are accelerated conversion of muscle glycogen to lactate, metabolic acidosis, increased ventilatory compensation for the metabolic acidosis, reduced exercise endurance, slowed V_ o2 kinetics during step increase in work rate, increased CO2 output relative to V_ o2 , hemoconcentration above the AT, and facilitation of oxyhemoglobin dissociation by the blood acidification (Bohr effect). Some of these are detrimental and some are beneficial in the performance of exercise. In the case of the latter, the maximal O2 extraction and peak V_ o2 would be reduced without the lactic acidosis [12]. Clinically, the AT is reduced when there is impaired O2 delivery to the muscles during exercise. The AT correlates Angiogenesis with peak V_ o2 in heart failure patients [22]. In applications in which a reliable peak V_ o2 cannot be obtained, the AT might replace it [23]. The AT measurement has proven to be of great value in defining the pathophysiology of exercise intolerance and its application in the differential diagnosis of physiological impairments that reduce exercise tolerance [24]. In addition, since it can be measured, noninvasively, the extent of its application has yet to be defined. References 1. Wasserman K (1994) Coupling of external to cellular respiration during exercise: the wisdom of the body revisited. Am J Physiol 266:E519–E539 2. Beaver WL, Wasserman K, Whipp BJ (1986) A new method for detecting the anaerobic threshold by gas exchange. J Appl Physiol 60:2020–2027 3. Beaver WL, Wasserman K, Whipp BJ (1986) Bicarbonate buffering of lactic acid generated during exercise. J Appl Physiol 60:472–478 4. Wasserman K, McIlroy MB (1964) Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14:844–852 5. Wasserman K, Hansen J, Sue DY, Stringer WW, Whipp BJ (2005) Chapter 2. Physiology of exercise. In: Wasserman K et al (eds) Principles of exercise testing and interpretation. 4th edn. Lippincott, Williams and Wilkins, Philadelphia 6. McGilvery RW (1983) The oxidation of glucose. In: McGilvery RW (ed) Biochemistry: a functional approach. Saunders, Philadelphia 7. Wasserman K, Beaver WL, Davis JA, Pu J-Z, Heber D, Whipp BJ (1985) Lactate, pyruvate, and lactate-to-pyruvate ratio during exercise and recovery. J Appl Physiol 59:935–940 8. Wasserman K, Beaver WL, Whipp BJ (1990) Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation 81(Suppl II): II-14–II-30 9. Stringer W, Casaburi R, Wasserman K (1992) Acid-base regulation during exercise and recovery in man. J Appl Physiol 72:954–961 10. Wasserman K, VanKessel A, Burton GB (1967) Interaction of physiological mechanisms during exercise. J Appl Physiol 22:71–85 11. Wasserman K, Stringer W, Casaburi R, Zhang YY (1997) Mechanism of the exercise hyperkalemia: an alternate hypothesis. J Appl Physiol 83:631–643 12. Stringer W, Wasserman K, Casaburi R, Porszasz J, Maehara K, French W (1994) Lactic acidosis as a facilitator of oxyhemoglobin dissociation during exercise. J Appl Physiol 76:1462–1467 13. Wasserman K (1999) Critical capillary PO2 and the role of lactate production in oxyhemoglobin dissociation during exercise. Adv Exp Med Biol 471:321–333 14. Koike A, Wasserman K, Taniguichi K, Hiroe M, Marumo F (1994) Critical capillary oxygen partial pressure and lactate threshold in patients with cardiovascular disease. J Am Coll Cardiol 23:1644–1650 15. Wasserman K, Beaver WL, Whipp BJ (1986) Mechanisms and patterns of blood lactate increase during exercise in man. Med Sci Sports Exerc 18(3):344–352 16. Wasserman K, Koike A (1992) Is the anaerobic threshold truly anaerobic? Chest 101:211–218 17. Koike A, Weiler-Ravell D, McKenzie DK, Zanconato S, Wasserman K (1990) Evidence that the metabolic acidosis threshold is the anaerobic threshold. J Appl Physiol 68:2521–2526 A 18. Zhang YY, Sietsema KE, Sullivan S, Wasserman K (1994) A method for estimating bicarbonate buffering of lactic acid during constant work rate exercise. Eur J Appl Physiol 69:309–315 19. Beaver WL, Wasserman K (1991) Muscle RQ and lactate accumulation from analysis of the VCO2-VO2 relationship during exercise. Clin J Sport Med 1(2):27–34 20. Wasserman K, Whipp BJ, Koyal S, Beaver WL (1973) Anaerobic threshold and respiratory gas exchange during exercise. J Appl Physiol 35:236–243 21. Wasserman K (1987) Determinants and detection of anaerobic threshold and consequences of exercise above it. Circulation 81(Suppl VI):VI-29–VI-39 22. Wasserman K, Sun X-G, Hansen J (2007) Effect of biventricular pacing on the exercise pathophysiology of heart failure. Chest 132:250–261 23. Older P, Hall A, Hader R (1999) Cardiopulmonary exercise testing as a screening test for perioperative management of major surgery in the elderly. Chest 116:355–362 24. Wasserman K (1997) Diagnosing cardiovascular and lung pathophysiology from exercise gas exchange. Chest 112:1091–1101 Androgen A class of hormone that stimulates or controls the development and maintenance of male characteristics and associated with anabolic activity. Cross-References ▶ Anabolic Steroids Angiogenesis THOMAS GUSTAFSSON, ERIC RULLMAN, ANNA STRÖMBERG Department of Laboratory medicine, Karolinska Institutet, Stockholm, Sweden Synonyms Capillarization; Neovascularization; Vessel growth Definition Postnatal vessel growth naturally occurs in the female reproductive system, in wound healing, and in skeletal muscle in response to exercise. Postnatal vessel growth has been assumed to occur as a functional modification of existing arteries such as the growth of preexisting vessels into functional collateral arteries (arteriogenesis) or the formation of new capillaries from an already established capillary network (angiogenesis) [5] (Fig. 1). Arteriogenesis in response to increased muscle activity has been reported in animal 83 A 84 A Angiogenesis Angiogenesis Vasculogenesis Arteriogenesis Bridging Sprouting Intussusception In situ EPC differentiation Collateral artery formation Angiogenesis. Fig. 1 A summary of the different mechanisms of vessel formation. Angiogenesis – proliferation of existing endothelial cells to form new capillary networks. Vasculogenesis – in situ differentiation of endothelial progenitor cells to form new endothelial cells. Arteriogenesis – remodeling of arterioles into collateral arteries models, but only a few reports of arteriogenesis in response to exercise exist from healthy humans. Until recently, any increase in capillarity in human or animal skeletal muscle in response to exercise was assumed to reflect vessel growth due to angiogenesis [1, 4]. However, in 1997 the Isner laboratory reported that human peripheral blood contained CD34+/VEGFR2+ cells that contributed to angiogenesis in vivo, and questioned the view that blood vessel formation in adults depended solely on angiogenesis [6] (Fig. 1). These cells were termed EPCs (endothelial progenitor cells), and after this original publication lot of research has been performed to characterize these cells and explore their functionality in various experimental models. Their mode of action is to circulate the blood stream and migrate into tissues of active vessel growth where they mature in situ to endothelial cells, a process termed vasculogenesis, similar to how the vascular network is formed in embryos. Basic Mechanisms The British surgeon John Hunter used the term “angiogenesis” in 1787 to describe blood vessels growing in the reindeer antler, and in 1935, Arthur Tremain Hertig described angiogenesis in the placenta of pregnant monkeys. It is now accepted that there are at least two different types of angiogenesis: true sprouting of capillaries from preexisting vessels, and nonsprouting angiogenesis or intussusceptive growth [5]. True sprouting angiogenesis, the major type of growth, is a complex process involving many cell types, signaling pathways, growth factors, and receptors. It is initiated by the activation of endothelial cells and vasodilatation of the parent vessel, followed by an increase in vascular permeability. The basement membrane and the extracellular matrix are degraded, releasing numerous growth factors and allowing endothelial cells to migrate to sites where new capillaries are needed. Nonsprouting angiogenesis is also observed in skeletal muscle and is called luminal division, longitudinal splitting or bridging. An important advantage of intussusceptive capillary growth is that it permits rapid expansion of the capillary network and thus enlarges the endothelial surface for metabolic exchange. Folkman’s 1971 hypothesis that tumor growth is dependent on angiogenesis [5] stimulated intensive research on the basic mechanisms underlying angiogenesis. Regardless of the type of angiogenesis, it is now believed that the process is mediated by diffusible angiogenic factors through an increased synthesis or release from intracellular or extracellular storage pools. In 1996, Hanahan and Folkman introduced the term “angiogenic switch” to describe how this occurs. Angiogenesis may be induced by an increase in angiogenic regulators or a decrease in angiostatic regulators [5]. The development of in vivo bioassays, in vitro analytic techniques, and murine transgenic models has allowed the identification and characterization of more than 30 angiogenic and inhibitory factors that directly or indirectly affect angiogenesis. Of these, vascular endothelial growth factor-A (VEGF-A) is one of the major regulators of angiogenesis [5]. Angiogenesis is a multistep process that includes integration of different signaling pathways such as VEGF-A and the angiopoietins Ang-1 and Ang-2. [3]. Conditions that increase the expression of Ang-2 or the levels of VEGF-A enhance the angiogenic process through Ang-2-induced endothelial destabilization. This in turn facilitates the effects of VEGF-A on endothelial activation [3]. Other mechanisms are needed to complete the complex multistep angiogenic process. Remodeling the extracellular Angiogenesis matrix, inflammation, and coagulation all clearly influence vascular growth in adults [4, 5]. Regarding vasculogenesis, the number of EPCs in the circulation is normally low but is increased when there is enhanced neovascularization and vessel repair. VEGF-A and stromal cell derived factor -1 (SDF-1) are important in guiding EPCs to regions of vessel growth (homing), and their expression is increased in tissues that have activated vessel formation. To enter the tissue from the circulation the EPCs need to traverse the endothelium, which is performed through binding to endothelial adhesion molecules. SDF-1 and VEGF induce the activation of Akt, which in turn enhances the expression of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Other adhesion molecules important for EPC homing are the E- and P-selectins and vascular adhesion molecule 1 (VCAM-1) [6]. Exercise Intervention Historical Review Vanotti and Magiday (1934) first described increased capillarity following muscle activity alone, and with voluntary endurance exercise training in rat and guinea pig muscles. More recent studies confirm that electrical muscle stimulation and exercise training induce increased capillarity in skeletal muscle in various animal species. The first human studies demonstrating an increase in capillarity in response to increased physical activity were published in the mid-1970s, and by the early 1980s, the cessation of exercise training was shown to induce a rapid regression in capillarity [1]. Biological Significance Increasing the number of capillaries in skeletal muscle improves oxygen uptake and utilization by increasing the surface area available for diffusion, decreasing the diffusion distance, and increasing the transit time for the exchange of oxygen, substrates, and waste products. Many of the metabolic pathways linked to levels of risk factors such as glucose and fatty acids, and lipoprotein turnover in humans, are controlled by the surface membranes of vascular endothelial cells in skeletal muscle [1]. Recent findings suggest that capillary formation, including utilization of EPCs, is crucial for the skeletal remodeling process. Regulatory Mechanisms Both animal and human experiments have contributed to the understanding of exercise-induced changes in A angiogenic growth factors, with ex vivo studies adding to the analysis of the underlying mechanisms [1, 4]. The increase in VEGF-A expression observed in exercised skeletal muscle together with the inhibition of exerciseinduced angiogenesis by gene deletion, VEGF-receptor inhibition, and trap models suggests that VEGF-A has a dominant role. However, the first characterized angiogenic factor, FGF-2, has consistently been shown to remain unchanged with exercise. The observations that VEGF-A mRNA levels increase transiently following acute exercise, whereas basal VEGF-A protein levels increase over a 5-week training program, suggest that protein translation must occur during the VEGF mRNA peak associated with each bout of exercise [2]. The angiopoietins are modulated during repetitive exercise bouts, producing a higher Ang-2/Ang-1 ratio that exerts a permissive effect on angiogenesis in both humans and rats [2]. In subjects in whom skeletal muscle has adapted to exercise training, the change in the Ang-2/Ang-1 ratio is reversed. This suggests that increased Ang-1 reflects a maturation of the capillary system during a later phase of the adaptation process [2]. Hypoxia, metabolic stress, and mechanical stretch appear to lead to sprouting angiogenesis, whereas shear stress appears to cause nonsprouting angiogenesis. A common feature in such situations is an increased expression of VEGF-A. Therefore, VEGF-A is crucial in both sprouting and nonsprouting angiogenesis [1, 4]. The regulation of VEGF-A by shear stress is clearly associated with nitric oxide production and the upregulation of endothelial nitric oxide synthase activity in endothelial cells. Several components of the hypoxia inducible factor 1 (HIF-1, the major transcription factor of hypoxic activation of cellular VEGF-A transcription) pathway are activated in response to a single bout of exercise in healthy human skeletal muscle. However, the mechanism responsible for the increase in VEGF-A in skeletal muscle fibers must be more complex than simply the activation of HIF-1. Numerous other factors and signaling pathways stimulated by exercise are known to activate the VEGF-A gene transcriptionally, for example 5’AMP-activated protein kinase (AMPK), adenosine, and peroxisome proliferator-activated receptor-coactivator (PGC-1) [1, 4]. In addition to the exercise-induced changes in gene expression, more rapid changes that may participate in the angiogenic response occur. For example, microdialysate obtained from skeletal muscle immediately following exercise stimulates endothelial cell proliferation and contains VEGF-A protein. During the initial phase of exercise, release of VEGF-A from the muscle is also observed. These changes occur long before any changes in gene transcription could result 85 A 86 A Angiotensin Converting Enzyme in protein synthesis and therefore support a release of VEGF-A from preexistent pools. Proteolysis of the extracellular membrane by proteases is a key event in sprouting angiogenesis and in addition to the degradation of membrane barriers, these enzymes can release bound growth factors through degradation of extra cellular matrix or binding proteins [4]. Another mechanism involved in the increase in available biofactors during bouts of exercise may thus be the activation of extracellular proteases in skeletal muscle tissue. Exercise-induced capillary growth probably results from the integrated activation of multiple systems and involves both nonsprouting and sprouting angiogenesis as well as vasculogenesis. The levels of EPCs and recruiting stimulatory factors for circulating EPCs increase following exercise, and in animal models factors involved in homing and maturation processes increase in areas of neovascularization [6]. Thus, it is not possible to exclude vasculogenesis from this process. However, more information is required to establish whether homing and maturation processes are activated in the muscles of healthy individuals during exercise, although the processes that have been suggested to be involved in homing of EPCs to peripheral tissues are similar to those demonstrated to be of importance for rolling and homing of leukocytes. Since these mechanisms have been demonstrated to become activated by exercise, it indirectly proves the involvement of vasculogenesis in exercise-induced capillary growth. Summary Exercise-induced angiogenesis results from the integrated responses of multiple systems and involves both nonsprouting and sprouting angiogenesis. VEGF-A increases in exercising muscle and appears to be a key factor in exercise-induced capillary growth. More studies are needed before vasculogenesis can be added as a mechanism of exercise-induced capillary growth. References 1. 2. 3. 4. Gustafsson T, Kraus WE (2001) Exercise-induced angiogenesisrelated growth and transcription factors in skeletal muscle, and their modification in muscle pathology. Front Biosci 6:D75–D89 Gustafsson T, Rundqvist H, Norrbom J, Rullman E, Jansson E, Sundberg CJ (2007) The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle. J Appl Physiol 103:1012–1020 Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, and Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998 Prior BM, Yang HT, Terjung RL (2004) What makes vessels grow with exercise training? J Appl Physiol 97:1119–1128 5. 6. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674 Wahl P, Bloch W, Schmidt A (2007) Exercise has a positive effect on endothelial progenitor cells, which could be necessary for vascular adaptation processes. Int J Sports Med 28:374–380 Angiotensin Converting Enzyme Angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II. The angiotensin-converting enzyme inactivates bradykinin, a powerful vasodilator. Angiotensin I A decapeptide with no biological activity, cleaved from precursor angiotensinogen by renin. It is converted by ACE into angiotensin II, a potent vasoconstrictor, after the removal of two amino acids at the C-terminal. Angiotensin II An octapeptide produced from angiotensin I after the removal of two amino acids at the C-terminal by ACE. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle. In addition, angiotensin II stimulates the release of aldosterone from the adrenal zona glomerulosa, which in turn increases salt and water retention. Angiotensinogen An a2-globulin produced by the liver and secreted into blood circulation. Angiotensinogen is the inactive precursor of angiotensin I and II. Anion An ion which carries a negative ( ) charge and migrates toward electrodes with a positive polarity (anode) when a current is applied. Aortic Coarctation Ankle/Brachial Index The ratio of the ankle systolic blood pressure to the brachial systolic blood pressure. ▶ Peripheral Arterial Disease Anoxia ▶ Hypoxia, Focus Hypoxic Hypoxia Antigen Usually a molecule foreign to the body but can be any molecule capable of being recognized by an antibody or T cell receptor. A Antioxidant Enzymes Enzymes that are powerful scavengers of free radicals and other oxidants. In general, the oxidant is the substrate of the enzyme. In some cases, the presence of cosubstrates (such as GSH) is essential for the activity of the enzyme. Antioxidants Any substance that can inhibit the oxidation of other compounds. There are enzymatic antioxidants (e.g., superoxide dismutate, catalase) and non-enzymatic antioxidans (e.g., glutathione). There are also a variety of dietary antioxidants and these include vitamin E and vitamin C and lipoic acid and lycopene. Antiretroviral Medication Antihypertensive Effects of Exercise Drugs used to treat retroviral infections (e.g., HIV) by interfering with specific steps in the life cycle of the virus. ▶ Hypertension Anxiolytic Antihypertensive Medications Drugs taken to lower blood pressure that include a and b blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, diuretics, and vasodilators among others. Anti-inflammatory Activation Anti-inflammatory activation is a macrophage inflammatory state characterized by the decrease of the secretion of many effectors and the release of high amount of IL-10. It can be triggered in vitro by IL-10 and/or glucocorticoids. Anti-inflammatory macrophages are associated with the resolution of inflammation and tissue repair. Exercise may have an anxiolytic effect – the anxiety level is reduced. Cross-References ▶ Depression ▶ Psychiatric/Psychological Disorders Aortic Coarctation A stenosis of the proximal descending aorta usually at, or beyond, the site of the duct, which may vary in anatomy, physiology, and clinical presentation. It may present with discrete or long-segment stenosis, sometimes associated with hypoplasia of the aortic arch and bicuspid aortic valve. 87 A 88 A AP-1 AP-1 Activator protein-1 (AP-1) is usually a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF, and JDP families. As a transcription factor, it regulates gene expression in response to a variety of stimuli, including inflammation via cytokines, growth factors, stress, and bacterial and viral infections. AP-1 in turn controls a number of cellular processes including differentiation, proliferation, and apoptosis. Apelin Apelin is a recently identified adipokine that has been reported to have a host of salutary effects on skeletal muscle and systemic carbohydrate and lipid metabolism. Apelin deficiency is associated with glucose intolerance, whereas the restoration of apelin concentrations reverses this condition. These effects may be caused in part by apelin’s ability to increase muscle mitochondrial content and improve fat oxidation. Apnea–Hypopnea Index The primary measure of sleep-disordered breathing severity calculated as the number of apneas and hypopneas per hour of sleep; commonly abbreviated AHI. Apoproteins Are specific proteins that populate and dictate the action and function of lipoproteins. Examples include apoprotein A1, B100, B48, C1-3, E, a, and others. Apoptosis AMIE J. DIRKS-NAYLOR School of Pharmacy, Wingate University, Wingate, NC, USA Synonyms Cell suicide; Programmed cell death Definition Apoptosis, programmed cell death, is a form of cell death that has an essential role in development, health, and disease [1]. Apoptosis plays a fundamental role in regulating cell number during developmental and postdevelopmental stages of the mammalian lifespan. For example, in the development of the central nervous system (CNS) half of the neurons produced during neurogenesis die via apoptosis before CNS maturation. In the mature adult, apoptosis is responsible for the death and shedding of cells in the epidermis and gastrointestinal tract. Apoptosis is also responsible for ridding the body of damaged or infected cells that may be harmful to the organism. Cells containing damaged DNA or dysfunctional mitochondria or cells infected with bacteria or viruses may die via apoptosis. Inadequate or excessive apoptosis contributes to pathophysiological conditions. For example, inadequate apoptosis is a vital mechanism of cancer development and progression. Excessive apoptosis has been implicated in the progression of many age-related diseases such as Alzheimer’s, Parkinson’s, and cardiovascular disease (e.g., atherosclerosis and diabetes mellitus). Furthermore, apoptosis has been implicated as an important mechanism in the loss of skeletal muscle mass and function with age. Exercise training has been shown to cause adaptations in apoptotic signaling making skeletal muscle more resistant to apoptotic stimuli [1]. Apoptotic signaling and the adaptations exerted by exercise training will be discussed. Basic Mechanisms Apoptosis is executed via specific signaling pathways that lead to distinct morphologic characteristics such as cell shrinkage, membrane blebbing, nuclear condensation, DNA fragmentation into ▶ mono- and oligo-nucleosomes, and phosphatidylserine translocation to the outer leaflet of the plasma membrane. Apoptosis is mediated by activation of a variety of cysteine proteases, known as caspases. Inactivated caspases, called ▶ procaspases, become activated by proteolytic cleavage. Initiation of apoptosis involves activation of a ▶ caspase cascade in which initiator caspases (e.g., caspase-8, caspase-9) first become activated and then cleave and activate effector caspases (e.g., caspase-3, caspase-7). The effector caspases carry out the proteolytic events that result in cellular breakdown and demise. There are 14 known mammalian caspases (i.e., caspase-1 through caspase-14), in which most participate in the apoptotic process depending on the stimulus and respective signaling pathway activated. The two major pathways extensively described include the intrinsic and extrinsic apoptotic signaling pathways (see Fig. 1). A Apoptosis TNF-α A TRAF2 TRADD TRADD TRAF2 TNFR1 Bak Bax Bcl-XL cFLIP cIAP-1/2 TRAF2 TRADD RIP1 tBid AIF EndoG Cyto c Caspase-8 Smac/Diablo Omi/HtrA2 Cyto c dATP FADD TRAF2 TRADD NF-κB FADD Bcl-2 Mitochondrion ARC RIP1 Cell survival Apaf-1 Procaspase-9 Procaspase-9 XIAP Procaspase-8 89 Procaspase-8 Large-scale DNA fragmentation Caspase-3 Caspase-9 Apoptosis Apoptosis. Fig. 1 Simplified scheme of intrinsic and extrinsic apoptotic signaling pathways. Arrows indicate a stimulatory effect while blunt lines indicate an inhibitory effect Mitochondria play a central role in the induction of apoptosis via the intrinsic pathway [2, 3]. Upon apoptotic stimulation, mitochondria can release cytochrome c into the cytosol, which forms a complex, the ▶ apoptosome, with procaspase-9, apoptotic protease activating factor 1 (Apaf-1), and dATP. Once the apoptosome is formed, procaspase-9 molecules can cleave and activate each other. Caspase-9 can then cleave and activate effector caspases such as procaspase-3, which leads to the typical morphological features of apoptosis. This process is highly regulated [2, 3]. First, cytochrome c release from the mitochondria is regulated. The B-cell lymphoma/leukemia-2 (Bcl-2) family of proteins was the first described to affect the release of cytochrome c. This family consists of a number of proteins, some of which are anti-apoptotic and others are pro-apoptotic. For example, Bcl-2 and Bcl2 related gene, long isoform (Bcl-XL) protect against cytochrome c release and are therefore anti-apoptotic, while Bcl-2 associated x protein (Bax), Bcl-2 antagonist killer 1 (Bak), and Bcl-2 interacting domain death agonist (Bid) favor cytochrome c release and are therefore proapoptotic. The ratio and interaction of the Bcl-2 family of anti-apoptotic and pro-apoptotic proteins determines the fate of cytochrome c release from mitochondria. Often the Bcl-2/Bax ratio is used as an indicator of apoptotic potential where a high ratio protects against apoptosis and a low ratio favors apoptosis. Apoptosis repressor with caspase-associated recruitment domain (ARC) is another protein that regulates cytochrome c release. Upon stimulation, ARC translocates from the cytosol to the mitochondrial membrane and prevents cytochrome c release. Recent data show that ARC may prevent apoptosis by binding to Bax and interfering with its activation, which would ultimately protect against cytochrome c release. Another level of regulation involves the inhibition of caspase-9 and caspase-3 by the inhibitor of apoptosis 90 A Apoptosis protein (IAP) family member X-linked IAP (XIAP). XIAP binds the activated caspases and inhibits the enzyme activity. Mitochondria can release additional proteins, along with cytochrome c, to relieve the inhibition exerted by the XIAP allowing apoptosis to occur. These proteins include Smac/Diablo and Omi/HtrA2. Mitochondria can also release apoptosis inducing factor (AIF) and endonuclease G (EndoG), which translocate to the nucleus to induce chromatin condensation and large-scale DNA fragmentation in a caspase-independent manner. The extrinsic pathway is mediated via the activation of membrane receptors, such as tumor necrosis factor receptor 1 (TNFR1) [4]. When activated by its ligand, tumor necrosis factor-alpha (TNF-a), TNFR1 can actually activate an apoptotic or an anti-apoptotic signal depending on the conditions. TNF-a binding leads to the formation of a complex on the cytosolic domain of TNFR1, which includes TNF receptor associated death domain (TRADD), TNF receptor associated factor-2 (TRAF2), and receptor interacting protein-1 (RIP1). Formation of this complex can lead to the activation of nuclear factorkappa B (NF-кB) resulting in an anti-apoptotic response. However, under conditions where NF-кB is suppressed, the TRADD-TRAF2-RIP1 complex translocates to the cytosol and recruits fas-associated death domain (FADD) and procaspase-8 [4]. Once caspase-8 is activated, it can then activate caspase-3. Caspase-8 can also cleave Bid forming the truncated Bid (tBid), which leads to the activation of the mitochondrial-mediated signaling pathway via the activation of Bax and/or Bak. Activation of the mitochondrial-mediated pathway may be a mechanism for amplification of the apoptotic signal or it may actually be a required event for the induction of receptor-mediated apoptosis. The latter is true in cell types that require the release of Smac/Diablo and/or Omi/ HtrA2 from the mitochondria in order to relieve the inhibition of caspase-3 by the XIAP. Cellular FADD-like interleukin-1 beta converting enzyme inhibitory protein (cFLIP) and cellular IAP1 and IAP2 (cIAP1/2) has been shown to inhibit activation of caspase-8. In summary, apoptosis has an essential role in health and homeostasis as well as contributing to the pathogenesis of a variety of diseases. Apoptosis is mediated via intrinsic and/or extrinsic signaling pathways, which are both highly regulated. The intrinsic pathway involves release of cytochrome c from the mitochondria, formation of the apoptosome, and activation of procaspase-9. The extrinsic pathway involves activation of membrane receptors, such as TNFR1, which often leads to the activation of procaspase-8. Caspase-9 and caspase-8 can both activate procaspase-3, which results in cellular demise and the associated morphological characteristics such as cell shrinkage, DNA fragmentation into mono- and oligonucleosomes, membrane blebbing, and formation of apoptotic bodies. Exercise Intervention Exercise training results in many beneficial adaptations, including adaptations in apoptotic signaling leading to a potentially greater resistance to apoptosis [1]. Several studies have shown that the rate of apoptosis decreases in response to exercise training or chronic electrical stimulation (CES). For example, mono- and oligo-nucleosomal DNA fragmentation, a common marker of apoptosis, has been observed to slightly decrease in soleus muscle of young animals as a result of exercise training. Further, in apoptotic prone white gastrocnemius and extensor digitorum longus aged animals, exercise training can return DNA fragmentation to that matching youthful levels. During muscle disuse DNA fragmentation significantly increases. Yet, a brief 5–10 min bout of exercise three times per day substantially attenuates disuse atrophy-induced DNA fragmentation. Exercise training can modulate apoptosis in skeletal muscle, perhaps to a greater degree in skeletal muscle predisposed to apoptosis (i.e., aged and disused skeletal muscle), by altering mitochondrial-mediated and/or receptor-mediated apoptotic signaling. Exercise training and/or CES appears to cause several adaptations in the intrinsic signaling pathway involving mitochondria [1]. First, exercise training causes adaptations in the Bcl-2 family proteins that may resemble an increase in the Bcl-2/Bax ratio, which would likely increase the resistance for cytochrome c release and formation of the apoptosome. For example, exercise training has been found to significantly increase Bcl-2 mRNA and protein and significantly decrease Bax mRNA in rat soleus muscle. The potential of exercise training to modulate Bcl-2 and Bax may not be as profound in young skeletal muscle as in old. Indeed, while 3 months of exercise training had no effect on Bcl-2 or Bax protein levels in young rat white gastrocnemius and rat soleus, the same stimulus restored Bcl-2 and Bax protein levels in aged rat white gastrocnemius and soleus to young expression levels. These data suggest that exercise training has the potential to reinstate a youthful anti-apoptotic potential in both fast and slow skeletal muscle. Secondly, in addition to potentially improving the Bcl-2/Bax ratio in apoptotic prone skeletal muscle, exercise training modulates ARC. ARC protein expression in the rat soleus is increased by exercise training or daily electrical stimulation of the rat tibialis anterior. By modulating the Bcl-2/Bax ratio and/or increasing ARC Apoptosis expression exercise training and/or CES limits mitochondrial cytochrome c release. For example, mitochondrial cytochrome c release has been shown to decrease in response to electrical stimulation. Intermyofibrillar mitochondria isolated from rat tibialis anterior muscle electrically stimulated daily results in a decrease in cytochrome c release under basal conditions and an attenuated release when subjected to a maximal reactive oxygen stimulus. Thirdly, Apaf-1 expression has been shown to be affected by exercise training. It was shown that 2 months of exercise training decreased Apaf-1 protein expression. Furthermore, exercise training can increase the resistance to mitochondrion-mediated apoptosis by increasing the expression of XIAP thus, limiting the activity of caspase-3 and -9 [1]. One month of treadmill training increases XIAP protein expression in young rat soleus muscle, producing a negative correlation between XIAP protein expression and apoptotic DNA fragmentation. This correlative relationship suggests an important mechanism for the anti-apoptotic benefit of exercise training. Lastly, adaptations may occur in apoptosis involving AIF and EndoG [1]. As previously discussed, mitochondrial release of AIF and EndoG induce chromatin condensation and large-scale DNA fragmentation in a caspaseindependent manner. Daily exercise training does not alter cytosolic levels of AIF or EndoG in the rat extensor digitorum longus or soleus or human skeletal muscle. However, intermyofibrillar mitochondria isolated from rat tibialis anterior following daily electrical stimulation decreases AIF release under basal conditions and attenuates AIF release when subjected to a maximal reactive oxygen stimulus. These observations suggest that AIF and EndoG adaptations to exercise training may be muscle specific or exercise training and electrical stimulation produce differential adaptations. In summary, exercise training and/or CES appears to cause adaptations in mitochondrial-mediated signaling that increase the resistance to apoptosis. Adaptations may include an increase in the Bcl-2/Bax ratio, increased expression of ARC and XIAP, and decreased expression of Apaf-1. Exercise training also appears to modulate aspects of the extrinsic pathway involving TNFR1; however, very few studies have been published [1]. Aging and disease states such as chronic heart failure are associated with elevated plasma levels of TNF-a. Exercise training has been utilized as a possible means of altering plasma TNF-a levels. Acutely, plasma levels of TNF-a can dramatically rise and subsequently return to baseline in response to strenuous exercise. However, exercise training has been observed to significantly lower plasma TNF-a levels in A many patients with heart failure. Further, individuals self-reporting a high level of physical activity have lower plasma TNF-a levels than sedentary individuals. Thus, basal plasma TNF-a levels vary with age, disease state, and chronic physical activity levels, perhaps predisposing individuals with high plasma TNF-a levels to apoptosis. Skeletal muscle TNFR1 expression levels and plasma levels of soluble TNFR1 (sTNFR1) are altered by age and exercise [1]. Aging increases TNFR1 in old rat extensor digitorum longus but not rat soleus. The increased TNFR1 expression in aged rat extensor digitorum longus may result in the preferential sarcopenia of this fast muscle compared to the slow rat soleus. Exercise training restores TNFR1 expression to youthful levels in the aged rat extensor digitorum longus. sTNFR1 may function as a TNF-a inhibitor or carrier, the plasma level of which is considered to be an important marker of TNF-a. Indeed, 4 months of combined strength and endurance exercise training can significantly decrease the plasma level of sTNFR1 in patients with heart failure. While strength training alone does not alter plasma sTNFR1 levels in old subjects, a significant negative correlation exists between strength gain and pretraining levels of sTNFR1 suggesting that subjects with low sTNFR1 levels may experience greater strength gains. Thus, sTNFR1 levels are modifiable by exercise and may predict how beneficial exercise training will be. The effects of chronic exercise training on the expression of adaptor molecules involved in TNFR1 signaling, such as TRADD, TRAF2, RIP1, and FADD have not been studied. However, exercise training has been shown to affect caspase-8 and -3 activation [1]. In the aged rat fast muscle, extensor digitorum longus, cleaved caspase-8 and -3 levels are elevated but not in the slow rat soleus muscle. However, increasing the activity level of old rat extensor digitorum longus restores cleaved caspase-8 and -3 levels to levels found in young rat extensor digitorum longus. In summary, exercise training has a plethora of beneficial effects in skeletal muscle including the ability to enhance resistance against apoptosis. It appears that exercise training induces protective adaptations in regulatory proteins in both the mitochondrial- and receptormediated signaling pathways. Exercise training may lead to an increase in the Bcl-2/Bax ratio and ARC expression, which may explain the decrease in cytochrome c release in exercise-trained muscle. Expression of Apaf-1 decreases and XIAP expression increases with exercise training, both adaptations afford skeletal muscle protection from apoptosis. Exercise training also may lead to a decrease in expression of TNFR1 and plasma levels of TNF-a. The content of activated caspase-8 and -3 are also decreased. 91 A 92 A Apoptosome Collectively, the data indicate that exercise training leads to a multitude of adaptations within skeletal muscle that decrease the apoptotic potential making skeletal muscle more resistant to cell death. References 1. 2. 3. 4. Dirks-Naylor AJ, Shanely RA (2009) Apoptosis in aging muscle and modulation by exercise, caloric restriction, and muscle disuse. In: Magalhães J, Ascensão A (eds) Muscle plasticity – advances in physiological and biochemical research. The Research Signpost, Kerala Green DR (2000) Apoptotic pathways: paper wraps stone blunts scissors. Cell 102:1–4 Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163 Micheau O, Tschopp J (2003) Induction of TNF receptor 1-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190 Apoptosome A multi-protein complex comprised of cytochrome c, Apaf-1, dATP/ATP, and procaspase-9. Arranged in Parallel This is a mechanical term indicating the arrangement for which it is true that forces exerted by two or more element must be added to obtain the total force. Note that if the elements can change in length the displacements cannot be added to obtain the total displacement (example, sarcomeres in parallel within a muscle fiber). Arranged in Series This is a mechanical term indicating that forces exerted on or by one element must also be borne by other element(s) with which it is arranged in series (equal force). If the elements can change in length, the displacements can be added to obtain the total displacement (example, sarcomeres in series within a muscle fiber). Arterial Blood Gases ▶ Gas Exchange, Alveolar Arterial Hypertension Some clinical studies clearly have demonstrated that intervention affecting known atherosclerotic risk factor, especially arterial hypertension, improves endothelial function and reduces atherosclerotic risk. In particular, the united Kingdome Prospective Diabetes Study (UKPDS) demonstrated that a 12% reduction in cardiovascular events can be expected from a 10 mmHg reduction in systolic blood pressure. In total a tight control of blood pressure reduced both diabetes-related morbidity and mortality with a reduction of macrovascular and microvascular complications. Of note, the Hypertension Optimal Treatment (HOT) trial, demonstrated a 67% risk reduction in cardiovascular mortality during a period of 4 years, only when the diastolic blood pressure was reduced to <80 mmHg in patients with diabetes. It is also important to consider the result of the Heart Outcomes Prevention Evaluation (HOPE) Study, which demonstrated that despite almost equivalent levels of blood pressure, patients with diabetes treated with an angiotensin-converting enzyme inhibitor had a significant reduction in the combined primary outcome (MI, stroke, cardiovascular death, total mortality, and revascularization) by 25–30%. In patients with diabetes mellitus type 1 and type 2, administration of ACE-inhibitors has been shown to enhance NOmediated endothelial function immediately after application, with further improvement evident after 4 weeks of therapy. Intensive treatment of hypertension in patients with newly diagnosed diabetes during an 8year period, which decreased systolic and diastolic blood pressure by 10 and 5 mmHg, respectively, significantly reduced both the absolute risk of stroke and the combined end point of diabetes-related death, death from vascular causes, and death from renal causes by 5%. The HOT, which treated elevations in diastolic blood pressure for an average of 3.7 years, reported similar reductions in the risk of composite end points for macrovascular disease in subgroup analyses of patients with type 2 diabetes. Cross-References ▶ Hypertension, Training Arterial PCO2 ▶ Gas Exchange, Alveolar Arteriosclerosis Arterial PO2 ▶ Gas Exchange, Alveolar Arteriosclerosis RALF KINSCHERF Head of the Department of Anatomy and Cell Biology, Philipps-University of Marburg, Marburg, Germany Synonyms Atherosclerosis Definition Arteriosclerosis (from the Greek arterio, i.e., artery, and sclerosis, i.e., hardening) refers to an acampsia of arteries. Therefore, the term arteriosclerosis describes any hardening, calcification, or loss of elasticity of middle or large arteries caused by subendothelial lipid deposits and immigration of leukocytes, especially ▶ monocytes, ▶ macrophages (MF), and lymphocytes, as well as a proliferation of smooth muscle cells. Basic Mechanisms Arteriosclerosis is a systemic, arterial, inflammatory disease [1], which starts with the childhood and increases with age. Hallmark of the disease is a chronic, proceeding degeneration of the arteries, including progressive alterations of the vessel wall, especially the intima. In symptomatical situations, arteriosclerosis can be obvious like coronary heart disease, myocardial infarction, peripheral arterial occlusion disease, or stroke. The clinical consequences of arteriosclerosis, especially cardiovascular diseases, are still the main cause of morbidity and mortality in the Western world. Several risk factors for the development of arteriosclerotic lesions are known like age, gender, diabetes, dyslipidemia, hypertension, hyperhomocysteinemia, overweight, sedentary lifestyle, smoking, and/ or stress. Additionally, arteriosclerosis is characterized by a complex multifactorial pathophysiology, including several pro-arteriosclerotic factors and cells, like adhesion molecules, cholesterol, cytokines, fat, growth factors, collagen, lipoproteins, endothelial cells, monocytes, MF, smooth muscle cells, and thrombocytes. This makes it hard to define a simple hypothesis for the complex pathogenetic processes of arteriosclerosis. However, inflammation in the vessel wall is suggested to play a major role in the initiation, A development, progression and the final steps of arteriosclerosis, i.e., plaque/lesion destabilization and eventually plaque rupture and stroke. During the growth of an arteriosclerotic plaque, inflammatory cells (i.e., monocyte-derived MF, T-lymphocytes) are localized in the vessel wall, which is mainly preceded by a dysfunction of endothelial cells, producing adhesion molecules that interact with inflammatory cells. MF secrete various cytokines, chemokines and growth factors that activate the proliferation of smooth muscle cells and induce the plaque progression, and finally the development of clinically relevant vulnerable plaques. Clinical cardiologists actually realize that coronary arteriosclerosis consists of two pathophysiological different syndromes, meaning stable and unstable plaques/lesions. The initiation, development, and progression of arteriosclerotic plaques are multifactorial, complex processes, which progress over a long period of time and in which several factors are mainly involved. About five major steps seem to be of significant relevance. Initial Step: Endothelial Dysfunction, Attachment, and Rolling of Leukocytes on the Endothelium Figure 1a shows a “normal” artery under physiological conditions, which does not have any arteriosclerotic plaques, i.e., the lumen (Lu) has no signs of stenosis. These arteries consist of an endothelium (E; endothelial cells), media (M; smooth muscle cells and more or less elastic fibers), and adventitia (Ad; connective tissue with vasa vasorum). Increased production of reactive oxygen species [partly due to enhanced activity of NAD(P)H oxidases] named oxidative stress, but also infection, genetic factors, high blood pressure, poor diet, and/or smoking are suggested to be responsible for the dysfunction of the endothelium, which leads to deposition of native ▶ low-density lipoproteins (LDL) or oxidatively/ enzymatically modified LDL (mLDL), inducing an increased expression of adhesion molecules. In this context, the selectin family of adhesion molecules are accountable for attachment and rolling of leukocytes (mainly monocytes), because of facilitated interactions between the sialylated carbohydrate portion of E- and P-selectin, which are expressed on endothelial cells and the carbohydrate structures on leukocytes. Step 2: Firm Adhesion and the Transmigration of Leukocytes [Monocytes, T-Cells] into the Subendothelial Space During this step, (inflammatory), leukocytes are directly in contact with/adhere to endothelial cells, mediated by adhesion molecules like intercellular adhesion molecule-1 93 A 94 A a Arteriosclerosis b c Arteriosclerosis. Fig. 1 (a) “Normal” artery (thoracic aorta) of a rabbit fed with standard chow (under physiological conditions); (b) arteriosclerotic artery (thoracic aorta) with an intermediate plaque of a cholesterol-fed rabbit; (c) arteriosclerotic artery (thoracic aorta) with a fibrous plaque of a cholesterol-fed rabbit: Ad adventitia, E endothelium, Fc fibrous cap, Fo foam cells, M media, Lu lumen, Nc necrotic core, Pl plaque (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), increasing the exposure to chemokines like interleukins (IL), e.g., IL-1, IL-6, and IL-18. These are essential for activation of integrins on the cell surface of leukocytes, which induce their transendothelial migration into the subendothelial space. Several studies have demonstrated an association between circulating pro-inflammatory molecules like IL-1, IL-6, tumor necrosis factor-a, C-reactive protein (CRP) or soluble adhesion molecules (sICAM-1, sVCAM-1), and future cardiovascular events in patients with coronary heart disease, but also in healthy individuals. Step 3: From Fatty Streak to Intermediate Lesion After transendothelial migration, leukocytes/MF (or even smooth muscle cells of the media) may modify deposited LDL to yield mLDL. Additionally, mLDL from the bloodstream may be localized in the subendothelial space. mLDL and transmigrated MF (e.g., by the secretion of chemokines) attract more and more MF, which results in the development of “fatty streak” consisting of a few MF, which may re-migrate to the bloodstream meaning that “fatty streaks” seem to be reversible up to a distinct degree. However, if “fatty streaks” do not disappear, they grow up to intermediated lesions due to the attraction of numerous leukocytes, which transmigrate into the subendothelial space. Figure 1b depicts an arteriosclerotic, intermediate lesion of the thoracic aorta of a cholesterol-fed rabbit. This arteriosclerotic plaque/lesion mainly consists of more or less lipid laden MF. Step 4: From Intermediate Lesion to Atheroma and Fibrous Plaque MF, which are localized in the subendothelial space, internalize mLDL by scavenger receptors, which are not downregulated. This leads to an intracellular accumulation of cholesterol and to the creation of “▶ foam cells,” which finally may result in cell death (apoptosis/necrosis) of the foam cells. When foam cells die, their contents are released. This attracts the next MF from the bloodstream and generates a necrotic lipid core in the depth of an arteriosclerotic plaque. Additionally, smooth muscle cells migrate from the media overgrowing the foam cells to build a ▶ fibrous cap. Figure 1c shows an arteriosclerotic, atheromatous/fibrous lesion of the thoracic aorta of a cholesterol-fed rabbit. This lesion is characterized by foam cells (Fo; lipid laden MF), a fibrous cap (Fc; consisting of fibrous connective tissue and migrated smooth muscle cells from the media) and a necrotic lipid core (Nlc). Proliferation and apoptosis of MF are important events controlling destabilization, inflammatory response, and plaque vulnerability. Rupture-prone plaques are called “vulnerable plaques.” A plaque destabilization by activation of matrixmetalloproteinases affecting the fibrous cap thickness may convert a chronic process into an acute disorder with clinical complication like acute coronary syndrome, coronary heart disease, myocardial infarction, or stroke. Step 5: From a Fibrous Plaque to a Complicated Lesion/Rupture Increased accumulation of foam cells, extracellular debris, necrotic lipid core in addition with a decrease in fibrous cap thickness by activation of matrix metalloproteinases enhances the risk for plaque rupture and thrombus formation. Plaque rupture with atheromatous debris and distal embolization is the major pathogenetic mechanism responsible for myocardial infarction and stroke. However, it is suggested that the plaque composition rather than lesion burden seems to be the determinant factor producing rupture and subsequent thrombosis. An infarct prognosis concerning cardiovascular risk can be individually calculated online according to the Arthritis PROCAM (Prospective Cardiovascular Münster) study [2], the ESC Euro SCORE [3] or the Framingham study [4]. Additionally, an individual risk calculation for stroke can be performed according to the Framingham study by the d’Agostini-Score [5]. A Arteriovenous Oxygen Difference The difference between the oxygen content of the arterial and mixed venous blood. Exercise Intervention Regular, long-term aerobic exercise even with low/moderate intensity (e.g., walking) has substantial inhibitory impact on development and progression of arteriosclerotic lesions and, thus, reduces the mortality from cardiovascular disease, but also all-cause mortality. In this context, it has been shown that men who participated in some form of regular moderate physical activity revealed direct vasoprotective effects, i.e., they had about 30% lower risk of mortality and a significantly diminished incidence of stroke. Long-term physical activity decreases the pro-arteriosclerotic activity of endothelial as well as peripheral blood mononuclear cells. The exercise-induced vasoprotective action seems to be due to a significant improvement of endothelial function (e.g., by enhancing NO bioavailability) and diminishing oxidative stress. However, regular aerobic exercise has beneficial (vasoprotective) effects such as induced suppression of inflammatory cytokines like interleukins or tumor-necrosis factor-alpha (TNF-alpha) and thereby offers protection against TNF-alpha-induced insulin resistance. Thus, regular physical activity results in increased insulin sensitivity, decreased fat content/obesity, as well as an attenuation of hyperlipidemia, but also enhances longevity by mechanisms independent of these risk factors. Vasoprotective, aerobic physical exercise sport is suggested, like: ● Walking (>20 min/day) ● Cycling, ball games, jogging, skating, swimming, team sport, etc. ● Gym (low weight and many repeats [n = 20; 3  n]) References 1. 2. 3. 4. 5. Ross R (1999) Atherosclerosis - an inflammatory disease. New Engl J Med 340:115–126 PROCAM (Prospective Cardiovascular Münster)-Study (2002) http://www.medical-tribune.ch/deutsch/fortbildung/kardiologie/ procam.php. Accessed 12 Sep 2011 Kardiovaskuläre Risikoberechnung nach dem ESC Euro SCORE (2003) http://www.bnk.de/transfer/euro.htm. Accessed 12 Sep 2011 Kardiovaskuläre Risikoberechnung nach der Framingham-Studie (2004) http://www.bnk.de/transfer/framingham.htm. Accessed 12 Sep 2011 Risikoberechnung für Schlanganfall nach der Framingham-Studie (d’Agostini-Score) (2004) http://www.bnk.de/transfer/stroke.htm. Accessed 12 Sep 2011 Arthritis DAVID L. SCOTT Department of Rheumatology, King’s College Hospital, Kings College London School of Medicine Weston Education Centre, London, UK Synonyms Arthrosis; Arthropathy; Inflammatory joint disease; Synovitis Definition Arthritis means inflammation of the joints. It spans a number of disorders. The commonest form of arthritis is osteoarthritis, which is primarily an example of joint failure. Its prevalence increases with age, and it is an inevitable consequence of longevity. Most other forms of arthritis have a more inflammatory drive. Classically, this is immune-driven inflammation; the best example of such inflammation is rheumatoid arthritis. It can also be due to crystal deposition; the best example of this is gout. Some forms of inflammatory arthritis involve only one or two joints; a good example of this is psoriatic arthritis. Connective tissue disorders that range from systemic lupus erythematosus to myositis are often accompanied by arthritis, though this is not usually their most prominent feature. Characteristics Arthritis results in joint inflammation. This is characterized by pain, swelling, tenderness, and stiffness. Acute arthritis can be associated with redness of the joints and may also give systemic features of inflammation with marked fatigue. The features of arthritis vary depending on the cause. Osteoarthritis mainly causes pain and bony swelling of the joints; the stiffness of osteoarthritis is most marked after exercise. Rheumatoid arthritis more often results in joint swelling, which is symmetrical and involves the small joints of the hands. The stiffness of rheumatoid arthritis is most marked in the morning. The distribution of arthritis is typical for the different types. Osteoarthritis involves large joints such as the knee 95 A 96 A Arthritis Arthritis. Table 1 Summary of main forms of arthritis Type Subgroup Comment Osteoarthritis Generalized Common, occurs in later life, generalized form shows female preponderance Individual joints (e.g., knee) Rheumatoid arthritis Seronegative arthritis Common, occurs at all ages, female preponderance Psoriatic arthritis Ankylosing spondylitis Uncommon, occurs at all ages, some forms like ankylosing spondylitis show male preponderance Reactive arthritis Colitic arthritis Crystal arthritis Gout Pyrophosphate crystal deposition disease Connective tissue diseases Systemic lupus erythematosus Common, occurs at all ages, gout shows male preponderance, pyrophosphate disease linked to osteoarthritis Uncommon, arthritis usually minor component, female preponderance Vasculitis Scleroderma Myositis Infections Viral arthritis Septic arthritis Relatively uncommon, viral arthritis usually mild, septic arthritis usually severe and seen in immunocompromised patients or hip together with the base of the thumb and the distal interphalangeal joints. Rheumatoid arthritis involves the small joints of the hands and feet in a symmetrical distribution. Gout involves one or two joints – classically the first metatarsal joint (base of the big toe) and is severe and short lived if correctly treated. The main forms of arthritis are shown in the table (Table 1). Clinical Relevance Arthritis results in pain and reduced function. Inflammation also results in pain and disability. As a consequence, inflammatory arthritis is more disabling than osteoarthritis. Persisting inflammatory arthritis also results in joint damage. As a consequence of pain and inflammation, and in the later stages of disease as a result of joint damage, mobility is lost and fitness declines. Arthritis is common. Some degree of osteoarthritis is inevitable in the elderly and up to 30% of the over 65 have clinically relevant osteoarthritis. Inflammatory arthritis, which is mainly rheumatoid arthritis, is less common – involving up to 1% of adults – but it causes more disability. Gout is also common. Other forms of arthritis, such as psoriatic arthritis, are seen less frequently. Arthritis has a complex relationship to sport and activity. Joint damage is linked to the development of osteoarthritis in later life. Therefore some sports increase the eventual likelihood of developing osteoarthritis. A good example is football; the knees are prone to be damaged while playing, and there is an increased risk of developing osteoarthritis. On the other hand, exercise also prevents obesity, and maintaining musculoskeletal fitness and avoiding obesity both reduce the chance of developing arthritis. As a consequence, overall, the benefits of sport and exercise outweigh the risks of developing osteoarthritis. Inflammatory arthritis such as rheumatoid arthritis has no specific relationship to sport and exercise. Therapeutical Consequences Drug Therapy The treatment of arthritis involves extensive medical care, based on optimizing drug treatment. The treatments span using analgesics to reduce pain, anti-inflammatory drugs to reduce the symptoms of joint inflammation, diseasemodifying drugs (DMARDs) to suppress immunemediated inflammation, biologic treatment to suppress immune-mediated inflammation, and a number of specific treatments such as allopurinol for gout. Although dietary modification is popular with patients, there is limited evidence that it is effective. Arthritis Glucosamine is widely used as a dietary supplement to treat osteoarthritis but is not usually considered to be effective. There is some evidence that certain dietary supplements can occasionally be useful in rheumatic diseases. An example is the use of creatine supplements in patients with myositis, which is one of the connective tissue diseases; when used in conjunction with physical exercise, these improve muscle power. Drugs in arthritis are involved in a range of different metabolic pathways. The main ones are as follows: ● Analgesics: These mainly act through central receptors for opiates. Examples are codeine-based analgesics. Paracetamol, which is the dominant mild analgesic, has a different mechanism of action, and most probably affects central cyclooxygenase pathways. ● Anti-inflammatory drugs: These mainly act through inhibiting cyclooxygenase pathways, though there are multiple other metabolic effects. They affect both central and peripheral cyclooxygenase metabolism and so reduce both pain and inflammation. ● Steroids: these bind to cell receptors and reduce inflammation and also change glucose metabolism. ● DMARDs: There is a wide range of DMARDs, and they act in many different ways. They are considered as a group because they suppress joint inflammation, but otherwise they are a diverse group of unrelated drugs. ● Biologics: New molecular approaches have greatly changed the treatment of arthritis. Different biologics target specific molecules involved in inflammation. The most widely used group, inhibitors of tumor necrosis factor, specifically inhibit this cytokine and therefore reduce inflammation. ● Allopurinol: This is an enzyme inhibitor that stops the synthesis of uric acid, and therefore means that uric acid crystals, the basis of gout, cannot be deposited. Almost all patients with arthritis need to take drug therapy from time to time. Most patients benefit from analgesics to treat pain. Anti-inflammatory drugs also reduce pain and they are widely used; caution is needed to balance their side effects with any benefits. They are best used for short periods rather than giving them for long periods. Patients with rheumatoid arthritis and other forms of inflammatory arthritis usually need not only analgesics and anti-inflammatory drugs but also take DMARDs and biologics. The aim is to suppress joint inflammation. There has been a marked change in the last few years with more intensive treatment used to suppress inflammation, often involving combinations of DMARDs and early use of biologics. A Gout is treated using anti-inflammatory drugs in the acute phase. Persisting gout needs treating with allopurinol. Steroids are also effective and widely used to treat arthritis. They can be given by local injection; for example, they can be injected into an inflamed knee. They can also be given by intramuscular injection or by mouth. They should only be used for short periods of time. Although patients need to take effective drugs, all the treatments used have significant risks of adverse effects. Anti-inflammatory drugs are linked to gastric ulcers and cardiac infarctions. DMARDs can result in bone marrow depression, and biologics increase the risk of infections. Steroids are particularly prone to cause side effects such as osteoporosis, diabetes, and cardiac disease. All these treatments therefore need to be used with caution. Exercise Intervention Historically, patients with arthritis were encouraged to rest; bed rest decreased the pain and inflammation of active arthritis. The Spa approach characterized the historical treatment of arthritis with a focus on rest. As a consequence of rest, patients became deconditioned and unfit and their arthritis was in the long-term worsened. The situation has now changed and patients with arthritis are encouraged to exercise and keep fit. The balance of evidence now strongly favors recommending exercise for all people with arthritis [1–4]. Two forms of exercise are used in arthritis. The first, and probably the most important, is general exercises to increase fitness. An example is to encourage patients to walk regularly. The second is specific exercises to improve strength; a good example is quadriceps strengthening in patients with osteoarthritis of the knee. Both of these approaches are effective and improve symptoms and reduce disability. The evidence to prefer one over the other is incomplete. However, not all patients are able to undertake aerobic exercise and vice versa. Therefore in clinical practice, it is important to have a choice of effective options available. Exercise in water, which has its historical background in hydrotherapy, is particularly effective in arthritis as the water provides support for active joints while allowing exercise to uninvolved areas. Strength training has been studied in detail in knee osteoarthritis [1], and it improves a wide range of attributes. These include pain, disability, strength, and walking abilities. A summary of recent trials is shown in the figure (Fig. 1). There is equally compelling evidence in rheumatoid arthritis [2]. A number of research studies have shown that exercise therapy, including aerobic or strengthening exercises, when used in conjunction with conventional drug 97 A 98 A Arthritis Walking endurance/time/speed Range of motion Muscle Strength Self-reported disability Stiffness Self-reported pain 0 5 10 Number of Studies Improvement 15 20 Studies Arthritis. Fig. 1 Main outcomes in trials of exercise in arthritis. Numbers of studies and those reporting positive results are shown for different outcomes [1] therapy, reduces pain and improves the quality of life in patients with rheumatoid arthritis. A key question is whether exercise worsens joint pain and inflammation in rheumatoid arthritis; the balance of evidence from many studies is that it does not do so. Given the extent of the information in favor of exercise helping patients with arthritis, it is unfortunate that there remains significant resistance from patients and clinicians in implementing exercise programs. There are a number of limitations. These include lack of interest from patients, a relative unwillingness of specialists to recommend exercise for patients, and difficulties in meeting the costs of the programs for both patients and clinical staff undertaking these programs. Measurements There are many different assessments of muscle function and the impact of exercise in arthritis. One important measurement is quadriceps motor function; this can be assessed clinically or by more rigorous approaches such as using a strain gauge system. It is possible to calculate maximum voluntary contractions using such an approach. A related issue is proprioceptive acuity, which indicates the patient’s joint position sense. Measurement tools such as electrogoniometer are useful in this context. As muscle function should improve performance, it is important to gain some understanding of patients’ relative performance over time. One approach to this is the objective measure of the “aggregate functional performance time,” which records the time taken to undertake four common activities of daily living. These comprise walking 50 ft on level ground, rising from a chair and walking 50 ft, and ascending and descending a flight of stairs. Shorter performance times indicate improved function. The end result of muscle weakness can be captured by assessing disability. Conventionally patient-reported disability is measured. The most widely used method is the Health Assessment Questionnaire (HAQ), which records disability over a 0–3 scale. Higher HAQ scores indicate greater disability. A number of more technical approaches are sometimes used. One example is measuring high-energy phosphate metabolites including ATP in the muscles before and after exercise; this can be achieved using phosphate magnetic resonance imaging. It is a highly specialized research method. Another example is the use of gait analysis to understand the mechanical issues underlying problems with performance in patients with arthritis; this tends to focus more on foot problems, but is useful to understand how patients are functioning. Asthma Bronchiale References 1. 2. 3. 4. Lange AK, Vanwanseele B, Fiatarone Singh MA (2008) Strength training for treatment of osteoarthritis of the knee: a systematic review. Arthritis Rheum 59:1488–1494 Oldfield V, Felson DT (2008) Exercise therapy and orthotic devices in rheumatoid arthritis: evidence-based review. Curr Opin Rheumatol 20:353–359 van den Berg MH, van der Giesen FJ, van Zeben D, van Groenendael JH, Seys PE, Vliet Vlieland TP (2008) Implementation of a physical activity intervention for people with rheumatoid arthritis: a case study. Musculoskeletal Care 6:69–85 Bearne LM, Scott DL, Hurley MV (2002) Exercise can reverse quadriceps sensorimotor dysfunction that is associated with rheumatoid arthritis without exacerbating disease activity. Rheumatology 41:157–166 Arthropathy ▶ Arthritis Arthrosis ▶ Arthritis Asthma Bronchiale ANDRÉ MOREIRA, LUÍS DELGADO Department of Immunology, and Immuno-allergology division, Faculty of Medicine, Hospital São João, E.P.E., University of Porto, Porto, Portugal Synonyms Asthma; Bronchial asthma; Exercise-induced asthma Definition ▶ Asthma has a significant genetic component, but since its pathogenesis is not clear, much of its definition is descriptive: “. . .a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung A that is often reversible either spontaneously or with treatment. . .” in the Global Initiative for Asthma (GINA) Workshop Report 2009 available at: www.ginasthma.org. The pattern of inflammation in allergic asthma is characterized by T helper (Th) 2 inflammatory phenotype with a predominance of Th2 cytokines – such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. The allergic inflammation is characterized by increased IgE concentrations, mast-cell degranulation, and eosinophil-mediated inflammation. In 2008, the PRACTALL initiative endorsed by the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology, defined ▶ exercise-induced asthma (EIA) as lower airway obstruction and symptoms of cough, wheezing, or dyspnea induced by exercise in patients with underlying asthma [1]. The same clinical presentation in individuals without asthma was defined as ▶ exercise-induced bronchoconstriction. These definitions are however limited by the heterogeneity in asthma expression. In fact, multiple asthma phenotypes exhibiting differences in clinical response to treatment exist and assessment should be multidimensional, including variability in clinical, physiologic, and pathologic parameters. Two different clinical endotypes of asthma in athletes, reflecting different underlying mechanisms, have been recently suggested by Tari Haahtela et al. The pattern of “classical asthma” characterized by early onset childhood asthma, methacholine responsiveness, atopy and signs of eosinophilic airway inflammation; and another distinct phenotype with onset of symptoms during sports career, bronchial responsiveness to eucapnic hyperventilation test, and a variable association with atopic markers and eosinophilic airway inflammation [2, 3]. From the clinical point of view, the main physiological feature of asthma is intermittent and reversible airway obstruction, while the dominant pathological feature is airway inflammation sometimes associated with airway structural changes. Airway responsiveness is the tendency for airways to constrict under the influence of nonsensitizing physical stimuli such as cold air and exercise, chemical substances such as methacholine, or sensitizing agents such as allergens. Airway hyperresponsiveness can be defined as an abnormal increase in the degree to which the airways constrict upon exposure to these stimuli. Pathogenesis A consistent body of evidence has shown that Olympic level athletes have an increased risk for asthma and allergy, especially those who take part in endurance sports, such as swimming or running, and in winter sports. 99 A 100 A Asthma Bronchiale The pathogenesis of EI-bronchoconstriction is likely multifactorial and is not completely understood. Classical postulated mechanisms behind exercise-induced asthma include the osmotic, or airway-drying, hypothesis [4]. As water is evaporated from the airway surface liquid, it becomes hyperosmolar and provides an osmotic stimulus for water to move from any cell nearby, resulting in cell shrinkage and release of inflammatory mediators that cause airway smooth muscle contraction. However, a proof of concept of this hypothesis would require that all athletes would develop bronchoconstriction at a certain point. This does not happen, suggesting the EIB explanatory model in athletes will probably include the interplay between environmental training factors including allergens and ambient conditions such as temperature, humidity, and air quality; and athlete’s personal risk factors such as genetic and neuroimmunoendocrine determinants. Genetic susceptibility to exercise-induced bronchoespasm has been linked with the gene for the aqueous water channel aquaporin. Airway hydration during exercise is mainly dependent on the water movement, following the osmotic force generated by sodium and chloride, through aquaporin channels expressed within the apical membrane of epithelial cells. It has been suggested that functional polymorphisms of the aquaporin gene may contribute to a phenotype where hyperhidrosis, sialorrhea, and excessive tearing are traits that may predict resistance of airways to nonspecific stimulus. However, it is also possible that mechanisms affecting both water and ion movement are commonly affected by nervous system dysfunction. Intensive training can have effects on autonomic regulation promoting the vagal predominance, thus regulating contractions and relaxations of the airway smooth muscle. The increased parasympathetic activity could act as a compensatory response to the sympathetic stimulation associated with frequent and intense training. This could induce not only the resting bradycardia typical of athletes, but also an increase in bronchomotor tone and, in turn, an increased susceptibility to the development of asthma. A dysfunctional neuroendocrine–immune interface may then play a role in the pathogenesis of exercise-induced bronchoconstriction, mainly due to release and action of neuropeptides from primary sensory nerve terminals, in the so-called neurogenic inflammation pathway. This is also clinically supported by a positive effect of inhaled anticholinergic drugs in some athletes. Exercise Response Exercise is a powerful trigger of bronchoconstriction and symptoms in asthmatic patients and may result in avoidance of physical activity resulting in detrimental consequences to their physical and social well-being. Diagnosis demands the synthesis of medical history with respiratory symptoms, physical examination, and appropriate laboratory or field tests. Methods and thresholds to document exercise-induced bronchoconstriction may be different for recreational or competitive athletes, particularly in regulated sports. For recreational exercisers, free running for children or a simple 10 min jog for adults may be adequate to document exercise-induced bronchoconstriction (10% drop in lung function measured by forced expiratory volume in the first second of forced vital capacity -FEV1). For others, the exercise challenge should elicit 90% of maximal heart rate or 40–60% of maximal ventilation during 6–8 min of exercise on a treadmill or stationary bicycle. For competitive athletes, precise criteria for diagnosing asthma have been set (Table 1). Drugs effective in the treatment of asthma are likely to be effective in the treatment of EI-asthma or EI-bronchoconstriction. Inhaled b2-adrenoceptor agonists are most Asthma Bronchiale. Table 1 Criteria set by the World Anti-Doping Agency to document asthma in athletes in 2011. www.wada-ama.org/. . ./WADA_Medical_info_Asthma_V3_ EN.0.pdf A rise in FEV1 to bronchodilator 12% of the baseline or predicted FEV1 and exceeds 200 ml A fall in FEV1  10% from baseline in response to exercise or eucapnic voluntary hyperpnea A fall in FEV1  15% from baseline after inhaling 22.5 ml of 4.5 g% NaCl or 635 mg of mannitol A fall in FEV1  20% from baseline in response to methacholine PC20  4 mg/ml, or PD20  400 mg (cumulative dose) or 200 mg (noncumulative dose) in those not taking inhaled corticosteroids (ICS), and PC20  16 mg/ml or PD20  1,600 mg (cumulative dose) or 800 mg (noncumulative dose) in those taking ICS for at least 1 month Note: In the case of an athlete with known but well-controlled asthma, recording a negative result to the bronchial provocation test(s), but still seeking approval for the use of inhaled b2-agonist(s), the following documentation must be included in the submitted medical file: consultations with their physician for treatment of asthma, hospital emergency department visits, or admissions for acute exacerbations of asthma or treatment with oral corticosteroids. Additional information that may assist includes: the age of onset of asthma; detailed description of the asthma symptoms, both day and night; trigger factors; medication use; past history of atopic disorders and/or childhood asthma; and physical examination, together with results of skin prick tests or RASTs to document the presence of allergic hypersensitivity. Negative bronchial provocation and allergy test results also must be included with the submission to the National Anti-Doping Agency Asthma Bronchiale effective in reversing EI-asthma/bronchoconstriction and are also used for prevention. The effectiveness of inhaled short-acting b-agonists such as salbutamol or terbutaline against EI-asthma/bronchoconstriction is optimal 20 min after inhalation and wane within a few hours. Long-acting b2-agonists, such as formoterol and salmeterol, protect for up to 12 h after a single inhalation. However, only formoterol acts as fast as quick-acting beta agonists; therefore, formoterol but not salmeterol, should be chosen to reverse EI-asthma/bronchoconstriction. Inhaled b2agonists may mask worsening airway inflammation, and should never be used regularly without an inhaled glucocorticoid. Regular treatments with inhaled ▶ glucocorticoids and/or ▶ leukotriene pathway antagonists control underlying asthma and reduce EI-asthma/bronchoconstriction. Zileuton is a leukotriene synthesis inhibitor, and montelukast, zafirlukast, and pranlukast are cysLT receptor-1 antagonists. H1-antihistamines have minimal effects on EI-asthma/bronchoconstriction, whereas cromones administered before exercise mildly reduce EI-bronchoconstriction. In difficult to control EIasthma/bronchoconstriction, combining inhaled glucocorticoids, oral leukotriene antagonists, and/or inhaled b2-agonists may be beneficial. Optimal control of underlying asthma minimizes airway narrowing during exercise. Worsening EI-asthma may be a sign of inadequate control of underlying asthma, and “step up” therapy should be considered. On the other hand, allergic rhinitis is also a very common disease among athletes, and may negatively impact athletic performance; its early recognition, diagnosis, and treatment are crucial for improving nasal function and reduce the risk of asthma during exercise and competition. Certain medications for athletes with asthma and rhinitis who participate in regulated competitions are not allowed and physicians, athletes, and coaches should be aware of the updated regulatory aspects of asthma treatment (Table 2). A few notes should be taken on the effects of exercise as a non-pharmacological treatment of asthmatic patients. At the current knowledge, evidence-based prescription of physical activity in asthma seems to be restricted to improvements in the physical fitness of the subjects. It is recommended that children and adolescents participate in at least 60 min of moderate intensity physical activity most days of the week and preferably daily (Report of the Dietary Guidelines Advisory Committee Dietary Guidelines for Americans, 2010). Engagement in physical activity promotes the child normal psychosocial development, neuromuscular coordination, and self-esteem. Changing from sedentary behaviors such as television viewing and A Asthma Bronchiale. Table 2 Drugs regulated for asthma treatment during training and competition by the World AntiDoping Agency in 2011 Beta agonists All beta-2 agonists are prohibited except salbutamol (maximum 1,600 mg over 24 h) and salmeterol when taken by inhalation in accordance with the manufacturers’ recommended therapeutic regime. Formoterol and terbutaline require a Therapeutic Use Exemption (TUE) with medical evidence of asthma. Reason why use of salbutamol and salmeterol is not suitable must be provided The presence of salbutamol in urine in excess of 1,000 ng/ml is presumed not to be an intended therapeutic use of the substance and will be considered as an Adverse Analytical Finding unless the Athlete proves, through a controlled pharmacokinetic study, that the abnormal result was the consequence of the use of a therapeutic dose (maximum 1,600 mg over 24 h) of inhaled salbutamol Glucocorticorticosteroid Inhaled glucocorticosteroids (GCS) are permitted. All glucocorticosteroids are prohibited when administered by oral, intravenous, intramuscular, or rectal routes computer games to moderate intensity physical activity has been associated with enhanced overall health and prevention of chronic diseases. In asthmatics, exercise training may reduce the perception of breathlessness through strengthening of respiratory muscle and decrease the likelihood of exercise-induced symptoms by lowering the ventilation rate during exercise. Currently, the GINA Guidelines do not include recommendations for exercise as part of the treatment for patients with asthma. Exercise is a powerful trigger for asthma symptoms. For this reason, caretakers may be reluctant to allow their asthmatic children to engage in sports practice, fearing an exacerbation of the disease. Every child with asthma should be questioned about exercise performance, tolerance, and symptoms, but there is no reason to discourage asthmatic children with a controlled disease to exercise [5]. References 1. 2. 3. Schwartz LB et al (2008) Exercise-induced hypersensitivity syndromes in recreational and competitive athletes: a PRACTALL consensus report (what the general practitioner should know about sports and allergy). Allergy 63(8):953–961 Haahtela T, Malmberg P, Moreira A (2008) Mechanisms of asthma in Olympic athletes–practical implications. Allergy 63(6):685–694 Lotvall J et al (2011) Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 127(2):355–360 101 A 102 A 4. 5. Atherosclerosis Carlsen KH et al (2008) Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: part I of the report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy 63(4):387–403 Moreira A et al (2008) Physical training does not increase allergic inflammation in asthmatic children. Eur Respir J 32(6):1570–1575 Atherosclerosis ▶ Arteriosclerosis ▶ Coronary Heart Disease Athlete One who participates in an organized team or individual sport that requires regular competition against others as a central component, places a high premium on excellence and achievement, and requires some form of systematic (and usually intense) training. Athlete’s Diet RICHARD B. KREIDER, Y. PETER JUNG Exercise & Sport Nutrition Lab, Department of Health and Kinesiology, Texas A & M University, College Station, TX, USA Synonyms Food regimes for active individuals; Macronutrient and micronutrient needs of athletes; Major nutrient requirements of sportsperson; Training table Definition The athlete’s diet is a well-designed diet that meets energy intake, macronutrient, and micronutrient needs and incorporates proper timing of nutrients in order to optimize performance, recovery, and/or training adaptations [1–3]. The athlete’s diet is the foundation upon which a sound performance enhancement training program can be developed. Research has clearly shown that not ingesting a sufficient amount of calories and/or enough of the right type of macronutrients may impede an athlete’s training adaptations while athletes who consume a balanced diet that meets energy needs can augment physiological training adaptations. Moreover, maintaining an energy-deficient diet during training may lead to loss of muscle mass and strength, increased susceptibility to illness, and increased prevalence of ▶ overreaching and/or ▶ overtraining. Incorporating good dietary practices as part of a training program is one way to help optimize training adaptations and prevent overtraining. Description Energy Demands. Athletes need to consume enough calories to offset daily energy demands [1]. Individuals who participate in a general fitness program (e.g., exercising 30–40 min per day, three times per week) can typically meet nutritional needs following a normal diet (e.g., 1,800–2,400 kcals/day or about 25–35 kcals/kg/day for a 50–80 kg individual) because their caloric demands from exercise are not too great (e.g., 200–400 kcals/ session). However, athletes involved in moderate levels of intense training (e.g., 2–3 h per day of intense exercise performed 5–6 times per week) or high volume intense training (e.g., 3–6 h per day of intense training in 1–2 workouts for 5–6 days per week) may expend 600–1,200 kcals or more per hour during exercise. For this reason, their caloric needs may approach 50–80 kcals/kg/day (2,500–8,000 kcals/day for a 50–100 kg athlete). For elite athletes, energy expenditure during heavy training and/or competition may reach as high as 12,000 kcals/day (150–200 kcals/kg/day for a 60–80 kg athlete). Additionally, caloric needs for large athletes (i.e., 100–150 kg) may range between 6,000–12,000 kcals/day depending on the volume and intensity of different training phases. Although some argue that athletes can meet caloric needs simply by consuming a well-balanced diet, it is often very difficult for larger athletes and/or athletes engaged in high volume/intense training to be able to eat enough food in order to meet caloric needs. Maintaining an energydeficient diet during training often leads to significant weight loss (including muscle mass), illness, onset of physical and psychological symptoms of overtraining, and reductions in performance [1, 4]. Nutritional analyses of athlete’s diets have revealed that many are susceptible to maintaining negative energy intakes during training. Consequently, it is important for professionals working with athletes to ensure that athletes are well fed and consume enough calories to offset the increased energy demands of training, and maintain body weight. Although this sounds relatively simple, intense training often suppresses appetite and/or alters hunger patterns so that many athletes do not feel like eating. Further, travel and training schedules Athlete’s Diet may limit food availability and/or the types of food athletes are accustomed to eating. This means that care should be taken to plan meal times in concert with training, as well as to make sure athletes have sufficient availability of nutrient-dense foods throughout the day for snacking between meals (e.g., drinks, fruit, carbohydrate/ protein energy bars, etc.) [4]. Carbohydrate. In addition to meeting energy needs, athletes need to consume the proper amounts of carbohydrate (CHO), protein (PRO), and fat in their diet [1, 2]. Individuals engaged in a general fitness program can typically meet macronutrient needs by consuming a normal diet (i.e., 45–55% CHO [3–5 g/kg/day], 10–15% PRO [0.8–1.0 g/kg/day], and 25–35% fat [0.5–1.5 g/kg/day]) [1]. However, athletes involved in moderate and high volume training need greater amounts of carbohydrate and protein in their diet to meet macronutrient needs. In terms of carbohydrate needs, athletes involved in moderate amounts of intense training (e.g., 2–3 h per day of intense exercise performed 5–6 times per week) typically need to consume a diet consisting of 55–65% carbohydrate (i.e., 5–8 g/kg/day or 250–1,200 g/day for 50–150 kg athletes) in order to maintain liver and muscle glycogen stores. However, resistance-trained or power athletes may only need about 40–45% carbohydrate in their diet in order to maintain a sufficient amount of muscle and liver glycogen during training [1, 2]. Athletes involved in high volume intense training (e.g., 3–6 h per day of intense training in 1–2 workouts for 5–6 days per week) may need to consume 8–10 g/day of carbohydrate (i.e., 400–1,500 g/day for 50–150 kg athletes) in order to maintain muscle glycogen levels. Preferably, the majority of dietary carbohydrate should come from complex carbohydrates with a low to moderate glycemic index (e.g., whole grains, vegetables, fruit, etc.). Protein. For people involved in a general fitness program, protein needs can generally be met by ingesting 0.8–1.0 g/kg/day of protein. Older individuals may benefit from a higher protein intake (e.g., 1.0–1.2 g/kg/day of protein) in order to help prevent ▶ sarcopenia. It is recommended that athletes involved in moderate amounts of intense training consume 1–1.5 g/kg/day of protein (50–225 g/day for a 50–150 kg athlete) while athletes involved in high volume intense training consume 1.5–2.0 g/kg/day of protein (75–300 g/day for a 50–150 kg athlete) [2]. Protein needs when living or training at altitude may be as high as 2.2 g/kg/day [2]. Although smaller athletes typically can ingest this amount of protein in their normal diet, larger athletes often have difficulty consuming this much dietary protein. Additionally, a number of athletic populations have been reported to A be susceptible to protein malnutrition (e.g., runners, cyclists, swimmers, triathletes, gymnasts, dancers, skaters, wrestlers, boxers, etc.). Therefore, care should be taken to ensure that athletes consume a sufficient amount of quality protein in their diet in order to maintain nitrogen balance (e.g., 1.5–2 g/kg/day). Fat. The dietary recommendations of fat intake for athletes are similar to or slightly greater than those recommended for nonathletes in order to promote health. Generally, it is recommended that athletes consume a moderate amount of fat (approximately 30% of their daily caloric intake). For athletes attempting to decrease body fat, however, it has been recommended that they consume 0.5–1 g/kg/day of fat. Strategies to help athletes manage dietary fat intake include teaching them which foods contain various types of fat so that they can make better food choices and how to count fat grams. Vitamins. Vitamins are essential organic compounds that serve to regulate metabolic processes, energy synthesis, neurological processes, and prevent destruction of cells. Although research has demonstrated that specific vitamins may possess some health benefit (e.g., Vitamin E, niacin, folic acid, vitamin C, etc.), few have been reported to directly provide ergogenic value for athletes. However, some vitamins may help athletes tolerate training to a greater degree by reducing oxidative damage (Vitamin E, C) and/or help to maintain a healthy immune system during heavy training (Vitamin C). Since dietary analyses of athletes have found deficiencies in caloric and vitamin intake, sports nutritionists’ often recommend that athletes consume a low-dose daily multivitamin and/or a vitamin enriched post-workout carbohydrate/protein supplement during periods of heavy training [1]. Minerals. Minerals are essential inorganic elements necessary for a host of metabolic processes. Minerals serve as structure for tissue, important components of enzymes and hormones, and regulators of metabolic and neural control. Some athletes have been found to have deficiencies in some mineral intakes. Dietary supplementation of minerals in deficient athletes has generally been found to improve exercise capacity. Calcium supplementation with Vitamin D has been recommended for athletes susceptible to premature osteoporosis. Iron supplementation in athletes prone to iron deficiencies and/or anemia has been reported to improve exercise capacity. Sodium phosphate loading has been reported to increase maximal oxygen uptake, anaerobic threshold, and improve endurance exercise capacity by 8–10%. Increasing dietary availability of salt (sodium chloride) during the initial days of exercise training in hot and humid environments has also been reported to help maintain fluid balance and prevent 103 A 104 A Athlete’s Heart dehydration. Finally, zinc supplementation during training has been reported to decrease exercise-induced changes in immune function. Consequently, in contrast to vitamins, there appear to be several minerals that may enhance exercise capacity and/or training adaptations for athletes under certain conditions [1]. Water. Water remains one of the most important nutrients for athletes. Exercise performance can be significantly impaired when 2% or more of body weight is lost through sweat. Weight loss of more than 4% of body weight during exercise may lead to heat illness, heat exhaustion, heat stroke, and possibly death. For this reason, it is critical that athletes consume a sufficient amount of water and/or glucose-electrolyte solution (GES) during exercise in order to maintain hydration status. Generally, athletes need to ingest 0.5–1 L/h of fluid per hour of exercise in order to prevent dehydration. This requires frequent ingestion of 6–8 oz of cold water and/or a GES sports drink every 5–15 min during exercise. Nutrient Timing. In addition to these general nutritional guidelines, ▶ nutrient timing has also been reported to play a role in optimizing performance and training adaptations [3]. Pre-exercise meals should be consumed about 4–6 h before exercise. It is also advisable to ingest a carbohydrate and protein snack 30–60 min prior to exercise (e.g., 30–50 g of carbohydrate and 5–10 g protein). This serves to increase carbohydrate availability toward the end of an intense exercise bout and provide amino acids to help decrease exercise-induced catabolism of protein. When exercise lasts more than 1 h, athletes should ingest GES sport drinks in order to maintain blood glucose levels, help prevent dehydration, and reduce the immunosuppressive effects of intense exercise. Following intense exercise, athletes should consume carbohydrate and protein (e.g., 1 g/kg of carbohydrate and 0.5 g/kg of protein) within 30 min after exercise as well as consume a high carbohydrate meal within 2 h following exercise. This nutritional strategy has been found to accelerate glycogen resynthesis as well as promote a more anabolic hormonal profile that may hasten recovery. Finally, for 2–3 days prior to competition, athletes should taper training by 30–50% and consume 200–300 g/day of extra carbohydrate in their diet. This ▶ carbohydrate loading technique has been shown to supersaturate carbohydrate stores prior to competition and improve endurance exercise capacity. Clinical Use/Application Athletes engaged in intense training need to consume enough calories, macronutrients, and micronutrients to meet energy needs. Athletes who maintain energy-deficient diets and/or do not consume enough carbohydrate, protein, vitamins, and/or minerals to meet nutritional needs may experience a lack of positive training adaptations and poor performance leading to overtraining. References 1. 2. 3. 4. Kreider RB et al (2010) ISSN exercise and sport nutrition review: research and recommendations. J Int Soc Sports Nutr 7:7 Campbell B et al (2007) International Society of Sports Nutrition position stand: protein and exercise. J Int Soc Sports Nutr 4:8 Kerksick C et al (2008) International Society of Sports Nutrition position stand: nutrient timing. J Int Soc Sports Nutr 5:17 Kreider RB (2001) Nutritional considerations of overtraining. In: Stout JR, Antonio J (eds) Sport supplements: a complete guide to physique and athletic enhancement. Lippincott, Williams and Wilkins, Baltimore, pp 199–208 Athlete’s Heart WILFRIED KINDERMANN Institute of Sports and Preventive Medicine, University of Saarland, Saarbrücken, Germany Synonyms Athletic heart syndrome; Marathoners’ heart Definition The Finish physician Henschen described enlarged hearts in cross-country skiers in 1899 by means of percussion. He concluded that prolonged exercise training causes both dilatation and hypertrophy of the heart. Henschen referred to this enlargement induced by endurance training as athlete’s heart. The nature of the athlete’s heart has been controversially discussed for many decades. According to the Frank–Starling Law, it was assumed that the enlargement of the heart reflected a pathological state. Based on electrocardiographic and X-ray examinations in a number of highly trained athletes, Reindell from Freiburg, however, realized as early as in the first half of the twentieth century that the enlarged heart caused by sports reflects a physiological hypertrophy. Numerous detailed studies of elite athletes, using newer methods, confirmed that the athlete’s heart is a physiological adaptation to chronic endurance exercise. The muscle mass of the heart increases and all heart cavities are enlarged, resulting in an eccentric hypertrophy. These changes have, since then, been well known as physiological cardiac remodeling [1, 4]. Mechanisms Endurance exercise requires an increased cardiac output for extended periods of time. The resulting volume load is the Athlete’s Heart 15 14 HV (ml/kg) 13 12 11 10 9 60 LV-EDD (mm) 58 56 54 52 50 48 IVS PW (mm) 12 11 10 9 8 END (83) TEAM (230) STR (31) OTH (17) Athlete’s Heart. Fig. 1 Mean values and standard deviation of heart volume (HV), left ventricular end-diastolic diameter (LV-EDD) and wall thicknesses (IVS interventricular septum, PW posterior wall) in endurance athletes (END), team sports (TEAM), strength athletes (STR), and other types of sports (OTH, e.g., bowling, dancing, golf, shooting) crucial mechanism for the development of eccentric hypertrophy. This is similar to pathological volume-overloaded hearts such as aortic regurgitation although only the left ventricle is primarily enlarged in this case. By contrast, the athlete’s heart is a balanced enlarged heart. Provided that duration and intensity of exercise are adequate, endurance training results in similar changes of left and right ventricle with regard to mass, volume, and function [4]. In particular, dimensions of heart cavities as well as wall thicknesses increase. The concomitant increase in wall thickness A maintains normal myocardial wall stress. Otherwise, the only increase in end-diastolic dimension would raise the wall stress according to the Law of Laplace. Furthermore, systolic and diastolic functions of left ventricle are not affected. Because of the heightened vagal tone, the ejection fraction may be in the lower normal range in some athletes, but will always return to normal during exercise. Several, but not all studies, evaluating transmitral flow by Doppler echocardiography, even demonstrated supranormal diastolic function of the athlete’s heart. Finally, the enlarged heart of endurance athletes shows normal left ventricular filling pressures at rest and during exercise. The increased blood pressure, especially during static exercise, is discussed as a further mechanism to develop changes of the heart. Concentric left ventricular hypertrophy, resembling the pattern of pathological pressureoverloaded hearts, was described in strength-trained athletes. It is assumed that the clearly increased afterload during mainly static exercise results in increased wall thickness without changes in end-diastolic ventricular dimensions. This type of an athlete’s heart, however, is not generally accepted. Methodological pitfalls and in particular the influence of drugs such as anabolic steroids possibly misused have to be taken into account. Anabolic steroids can develop concentric hypertrophy of the left ventricle and are mostly, but not always, associated with an impaired diastolic function. If comparing the influence of different sports on left ventricle, the ratio between enddiastolic wall thickness and internal ventricular diameter was only significantly increased in body builders using anabolic steroids. All other athletes including anabolicfree strength-trained showed no concentric hypertrophy (Fig. 1). As a result of existing data, a specific influence of strength training is rather unlikely [5]. Exercise Response An enlargement of the heart following sport is less common than generally assumed. Regular and intensive endurance training over the years for example, at least 5 h per week, is necessary. On the other hand, there are considerable individual differences with respect to a sports-related enlargement of the heart which are probably caused genetically. Even a running training of 100 km or more per week does not necessarily induce an enlarged heart. Accordingly, there is only a loose relationship between heart size or various echocardiographic parameters (e.g., left ventricular muscle mass, left ventricular end-diastolic diameter) and performance. Therefore, in the diagnosis of endurance performance, the knowledge of heart size cannot replace other physiological measures such as maximal oxygen uptake [1]. 105 A 106 A Athlete’s Heart The heart size in athletes can be determined by echocardiography. The end-diastolic left ventricular volume, obtained from the modified Simpson rule, highly correlates with the radiologically determined total heart volume, which is usually expressed relative to body weight. The normal values in untrained healthy males and females are 10–12 (gray zone to 13) and 9–11 (gray zone to 12) ml/kg. There are no gender differences with regard to the percentage enlargement of the heart through training. The largest body weight-related heart volumes amount to approximately 20 (males) and 19 (females) ml/kg and are found in long-distance runners [1]. If expressed in absolute terms, however, the most enlarged athlete’s hearts were found in endurance-trained or combined endurance- and strength-trained athletes with high body weight, e.g., rowing, cycling, swimming, and triathlon. Values of about 1,300 ml or more are possible. Accordingly, left ventricular end-diastolic diameter and wall thickness are also the greatest in endurance-trained athletes [3]. In team sports, especially soccer players, athletes may have slightly enlarged heart dimensions. Athletes hardly performing endurance training have no enlarged hearts, for example, types of sports such as athletics (sprinting, jumping, throwing, decathlon), gymnastics, alpine skiing, and weight lifting (Fig. 1). Children and adolescents are also likely to develop the same cardiocirculatory adaptations to endurance training, including moderate heart enlargement. Furthermore, if older persons perform regular dynamic training of a certain duration and intensity, they can also develop enlarged hearts. From a technical point of view, the athlete’s heart works with a larger swept volume and a reduced frequency. The dimensional changes lead to a significant increase in stroke volume and decrease in heart rate at rest and during exercise. Since the maximal heart rate remains largely unchanged, a high maximal cardiac output is achieved. The submaximal cardiac output, however, shows no relevant difference between trained and untrained heart [1]. The left ventricular hypertrophy can already decrease after a short period of detraining [3]. After long-term deconditioning, the regression of athlete’s heart can be complete. The left ventricular dilatation, however, is frequently only partially reversible [1]. In some cases, the dimensions remain markedly enlarged (end-diastolic diameter 60 mm). In contrast, the wall thickness shows complete normalization. In addition to genetic influences, remaining physical activity and a usually increased body weight have to be considered causally. A relatively low training volume after the end of sporting career seems to be sufficient for a persistent moderate enlargement. There is no evidence that former elite athletes with athlete’s heart die prematurely. On the contrary, it was shown that the life expectancy of former endurance athletes is even higher than those of inactive subjects. Athlete’s heart is commonly associated with electrocardiographic (ECG) alterations [1, 3]. The most common changes are rhythm and conduction abnormalities (except intraventricular), increased QRS voltages, incomplete right bundle branch block, early repolarization patterns, and deep Q-waves. These alterations are mostly physiological and due to lower intrinsic heart rate, increased vagal tone, and cardiac remodeling. The ECG changes in female athletes are rarer. Rhythm and conduction abnormalities disappear during physical exercise because of decreased parasympathetic and increased sympathetic activity. Arrhythmias like frequent premature beats and nonsustained ventricular tachycardias may be part of the athletic heart syndrome. Nevertheless, pathological causes should be excluded. T-wave inversion, reported between 2% and 4% and mostly located in precordial leads, may be training related; however, further cardiac diagnosis is required. ECG abnormalities including T-wave inversions are more commonly present in black compared with white athletes. Diagnostics The differential diagnosis between physiological athlete’s heart and pathological conditions may be difficult in some athletes. Cardiovascular diseases such as hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertension, and valvular heart diseases induce changes mimicking certain morphological adaptations of the athlete’s heart [2]. The knowledge of upper limits of cardiac dimensions helps to exclude pathological changes (Table 1). The diastolic dimensions of the left ventricle characterizing the Athlete’s Heart. Table 1 Upper limits of echocardiographic criteria of the athlete’s heart (exceptional individual values in brackets) Men Women Heart volume (ml/kg) 20 19 Heart weight (g/kg) 7.5 7 LV muscle mass (g/m) 170 135 LV-EDD (mm) 63 (67) 60 (63) Wall thickness (mm) 13 (15) 12 Left atrial dimension (mm) 45 (50) 43 (46) LV left ventricular, EDD end-diastolic diameter Athletic Amenorrhea hypertrophy may be substantially increased in some athletes. Approximately 15% have an end-diastolic diameter of 60 mm or greater, and 2% show wall thicknesses of between 13 and 15 mm [3]. Combined strength- and endurance-trained athletes with great body dimensions like rowers or canoeists commonly show greater morphological adaptations than others because of isotonic and isometric training of both the arms and legs. Values of up to 67 mm for end-diastolic diameter and up to 15 mm for wall thickness are from such athletes [3]. Black athletes exhibit a greater left ventricular wall thickness and more frequently exceed the normal limit of 12 mm than white athletes. The left atrium is enlarged in about 20% of the athletes and is part of the physiological remodeling. Two percent show a marked dilatation of 45 mm or greater (Table 1). There is a close association between the enlargement of the left ventricle and the size of the left atrium. Despite left atrial enlargement, atrial fibrillation is not more common in young athletes than in the general population. Left ventricular wall thicknesses of 13 mm or more are suspect for pathological hypertrophy if the size of the left ventricle is normal or even rather small. The most important differential diagnosis is the presence of hypertrophic cardiomyopathy, the most common cause for sudden cardiac death in young athletes [2]. In contrast to athlete’s heart, the diastolic function is mostly restricted, the left atrium can be marked enlarged, the wall thickness does not decrease after cessation of training, and the ECG often shows distinct changes. A further clinical scenario is the differentiation between athlete’s heart and dilated cardiomyopathy [2]. Diagnostic doubtful cases are athletes with an enddiastolic diameter of 60 mm and low-normal systolic function, e.g., ejection fraction of 50–55%. The systolic left ventricular function of the athlete’s heart, however, is always normalized during exercise. Moreover, the ergometric performance is always increased in physiologically enlarged hearts. Endurance training in athletes with aortic or mitral regurgitation can induce marked enlargement of left ventricle. Due to the combined volume load by training and valvular regurgitation, it is often difficult to evaluate the severity of regurgitation based on left ventricle dimensions. Mild valvular regurgitation per se does not influence the ventricle size. Therefore, if the left ventricular end-diastolic diameter of highly trained athletes with known valvular regurgitation is 60 mm, a significant regurgitation should be taken into account. In this case, consequences would result for the eligibility in competitive sports [2]. A Cross-References ▶ Cardiac Hypertrophy, Physiological References 1. 2. 3. 4. 5. Kindermann W (2007) Physiologische Anpassungen des HerzKreilauf-Systems an körperliche Belastung. In: Kindermann W, Dickhuth HH, Nieß A, Röcker K, Urhausen A (eds) Sportkardiologie. Steinkopff, Darmstadt, pp S1–S20 Maron BJ, Zipes DP (2005) 36th Bethesda conference: eligibility recommendations for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol 45:2–64 Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spirito P (1991) The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med 324:295–301 Scharhag J, Schneider G, Urhausen A, Rochette V, Kramann B, Kindermann W (2002) Right and left ventricular mass and function in male endurance athletes and untrained individuals determined by magnetic resonance imaging. J Am Coll Cardiol 40:1856–1863 Urhausen A, Kindermann W (1999) Sports-specific adaptations and differentiation of the athlete’s heart. Sports Med 28:237–244 Athletic Amenorrhea MARY JANE DE SOUZA, REBECCA J. TOOMBS Women’s Health and Exercise Laboratory, Noll Laboratory, Department of Kinesiology, Penn State University, University Park, PA, USA Synonyms Amenorrhea; Exercise-associated functional hypothalamic amenorrhea; Exercise-associated menstrual disorder; Female athlete triad-associated amenorrhea Definition Amenorrhea is the most serious menstrual disturbance observed in physically active women and athletes [1]. There are two classifications of amenorrhea, primary and secondary. ▶ Primary amenorrhea is defined as the failure to achieve menarche by age 15 in the presence of normal development of secondary sex characteristics [1]. The definition of ▶ secondary amenorrhea in the exercise literature has varied but should be defined conservatively as no menses for 90 days or 3 months, or less than five menses in 12 months. It is important to define amenorrhea conservatively (no menses for 90 days) versus liberally (no menses for 12 months) since serious clinical sequelae result from the presence of this disorder, particularly, low bone mass. In athletes, the amenorrhea is termed as functional hypothalamic amenorrhea since the origin of the disorder 107 A Athletic Amenorrhea 150 10 125 E1G 9 PdG 8 7 100 6 75 5 4 50 3 2 25 Pregnanediol glucuronide (μg/ml) A Estrone-1-glucuronide (ng/ml) 108 1 0 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Day of Cycle Athletic Amenorrhea. Fig. 1 Representative profile of estrogen and progesterone excretion in urine samples collected daily for 28 days in an amenorrheic athlete. E1G Estrone-1-glucuronide, PdG Pregnanediol glucuronide resides in the hypothalamus [2, 3]. ▶ Functional hypothalamic amenorrhea in athletes is classically characterized by decreased gonadotropin-releasing hormone pulsatility and decreased pulsatility of the gonadotropins, particularly luteinizing hormone, in the face of chronic hypoestrogenism. The pituitary gland exhibits normal or exaggerated responsiveness to perturbation by gonadotropin-releasing hormone. Amenorrhea, whether primary or secondary, is associated with chronically suppressed levels of the ovarian steroids, estrogen and progesterone [2]. Figure 1 provides an example of a profile of estrogen and progesterone excretion in urine samples (urinary estrone and pregnanediol glucuronides) collected daily for 28 days in an amenorrheic athlete. Mechanisms In 1980, Dr. Michelle Warren first published the hypothesis that a long-term “energy drain” was associated with the reproductive suppression and amenorrhea observed in exercising women. Since then, this concept has been refined and the etiology of amenorrhea is predominately thought to be secondary to low energy availability [3]. ▶ Low energy availability means that the volume of energy an exercising woman has available is not enough to adequately support all of her physiological functions and results in her body making metabolic shifts to preserve the most important functions that are needed to sustain life and, as such, suppresses other less essential functions to conserve fuel, like reproductive function [2, 3]. Thus, in exercising women, the amenorrhea is attributable to low energy availability where inadequate caloric intake combined with high energy expenditure causes an overall energy deficit. The energy deficit, in turn, stimulates compensatory metabolic shifts that cause weight loss and energy conservation, translating effects that result in hypothalamic suppression of ovarian function and amenorrhea [2, 3]. Mechanistically, when energy intake is inadequate to meet energetic demands, the body repartitions energy away from reproduction and growth and toward other more essential energy-consuming processes such as thermoregulation, cell maintenance, and locomotion. The primary metabolic shifts that are associated with energy conservation in amenorrheic athletes include a decrease in resting energy expenditure (REE), and suppression of triiodothyronine (TT3), insulin-like growth factor-1 (IGF-1), and leptin concentrations and elevated ghrelin and cortisol concentrations [4]. Short-term and prospective training studies have provided convincing evidence of the effects of low energy availability on metabolic hormones and luteinizing hormone (LH) pulsatility [5–7]. Short-term manipulations of both dietary intake and energy expenditure at energy availability levels of mild, moderate, and severe levels of energy restriction (10, 20, or 30 kcal/kg LBM/d, respectively) for 4–5 days have consistently demonstrated suppressed peripheral concentrations of metabolic hormones, including TT3, IGF-1, insulin, leptin, and decreased LH pulsatility [5]. Interestingly, the effects observed occurred in a dose–response manner with the most dramatic effects noted at the severe level of energy restriction. Athletic Amenorrhea Cause and effect relationships of low energy availability to actual menstrual function have been provided by the prospective training studies in monkeys [6, 7]. In these exercise training studies, amenorrhea was induced in monkeys during exercise training for a few months in an environment of inadequate energy availability, and the onset of the amenorrhea was directly related to the volume of calories restricted during the exercise training. Refeeding the amenorrheic monkeys by increasing their food intake without any moderation of their daily exercise training was associated with resumption of menses in the previously amenorrheic monkeys [6, 7]. It is of great interest that there was a dose-dependent relationship of the volume of energy intake and the resumption of ovulatory cycles in the amenorrheic monkeys such that the monkeys that ate the most calories recovered ovulatory function in the shortest period of time. Commensurate with the resumption of menses, total TT3, a key marker of metabolic status, was significantly related to both the induction and reversal of amenorrhea. The short-term and prospective studies provide evidence that the suppression of reproductive function is linked with low energy availability when there is inadequate caloric intake in the face of increased exercise energy expenditure. Exercise Response/Consequences In the United States, the passage of Title IX in 1972 during the Richard Nixon administration dramatically increased opportunities for girls and women to engage in physical activity and sport. Research during the subsequent 3–4 decades has focused on the unique effects of many aspects of exercise on girls and women’s health, particularly the impact of exercise on the menstrual cycle. One of the earliest reports of menstrual disorders in athletic women was published in 1962. In that report, a high prevalence of menstrual disorders was observed in athletes compared to nonathletes. Since that report, a plethora of studies have been published that confirm a high prevalence of the most serious menstrual disturbance, amenorrhea, in a wide variety of athletes, particularly those athletes involved in lean build sports like gymnastics, ballet, cross-country running, and figure skating [2, 3]. However, amenorrhea has been observed in virtually all sporting women, including women who participate in recreational physical activity [2, 3]. Amenorrhea is one of the most serious clinical problems observed in physically active women and athletes since amenorrhea plays a causative role in low bone mass observed in many female athletes [3, 8]. Inadequate energy intake precedes the clinical sequelae of amenorrhea and low bone mass. Inadequate energy intake in physically A active women and athletes is typically associated with internal and external pressures to maintain a low body weight, and translates into disordered eating behaviors that include a high drive for thinness and dietary cognitive restraint [3, 4]. A syndrome of disordered eating, amenorrhea, and low bone mass was defined in 1997 by the American College of Sports Medicine as the Female Athlete Triad [3]. Helpful information for athletes, coaches, and parents is available from the Female Athlete Triad Coalition at http://www.femaleathletetriad.org. Amenorrhea in athletes is associated with several bone health problems including stress fractures, loss of bone mass, the failure to achieve peak bone mass, and ▶ osteoporosis [3, 8]. Typically, bone mineral density (BMD) in amenorrheic athletes is 2–6% lower at the spine, hip, and total body when compared to athletes that are regularly menstruating [8]. Moreover, amenorrheic athletes have significantly lower lumbar spine and hip BMD Z-scores than age-matched sedentary women. In amenorrheic athletes, the prevalence of ▶ osteopenia is estimated to range from 1.4% to 50%, and the prevalence of osteoporosis is lower. Stress fractures are also 2–4 times more common in athletes with amenorrhea than athletes who are menstruating [3]. Three-dimensional imaging of bone in amenorrheic athletes also reveals a more definitive picture of the bone health of athletes. Indeed, trabecular BMD and bone strength are lower among athletes with amenorrheaassociated bone loss. Guidelines published for premenopausal women by the International Society for Clinical Densitometry are used as the reference criterion to diagnose low BMD or osteoporosis in athletes. These criteria utilize a Z-score of 2.0 or lower to diagnose low BMD, and when a secondary risk factor is also present, such as hypogonadism or nutritional deficiency, a diagnosis of osteoporosis may be applied. Chronic hypoestrogenism has typically been assumed to be the primary cause of bone loss in amenorrheic athletes. However, the effects of food restriction and energy deficiency on BMD represent an estrogenindependent mechanism for bone loss secondary to metabolic-related hormonal perturbations which include suppressed IGF-1 and leptin [8]. IGF-1 and leptin are important metabolic hormones that play a key role in optimizing bone formation. Figure 2 displays the mechanism by which high energy expenditure coupled with low energy intake result in bone loss among exercising, amenorrheic women. Thus, the mechanism underlying low bone mass in amenorrheic athletes is twofold, and includes both hormonal and nutritional components [8]. Bone is an active 109 A 110 A Athletic Amenorrhea Athletic Amenorrhea. Fig. 2 Mechanism by which bone loss occurs in exercising, amenorrheic women. High energy expenditure coupled with low energy intake results in hormonal and metabolic alterations that contribute to the uncoupling of bone turnover and subsequent bone loss. TT3 Triiodothyronine, IGF-1 Insulin-like growth factor-1 (From [9] Reproduced with permission) tissue, undergoing cycles of resorption and formation. In the face of both an estrogen and energy deficiency, an uncoupling of bone turnover occurs, creating an unfavorable environment of increased bone resorption and decreased bone formation, ultimately resulting in low bone mass [8]. The nutritional etiology of amenorrhea warrants emphasis, and treatment strategies should be focused on improving nutritional status in these physically active women and athletes. The best treatment approach is increased food intake and weight restoration, which are likely the best strategies for both resumption of menses and improved bone health [2, 3, 8]. Diagnostics Due to the multiple causes of amenorrhea and its presence in many disease states, the diagnosis of functional hypothalamic amenorrhea is one of exclusion [1, 3]. The diagnosis of amenorrhea in athletes requires a thorough physical exam, review of the patient’s medical history, and appropriate laboratory tests to rule out other underlying pathologies. Risk factors associated with functional hypothalamic amenorrhea include psychological stress, weight loss, and excessive exercise when coupled with inadequate nutrition [3]. In light of these risk factors, information regarding dietary habits, weight fluctuations, regular exercise regimen, and possible social or work-related stressors should be obtained during the physical exam [3]. When diagnosing amenorrhea, a pregnancy test should first be performed to exclude pregnancy as a cause. Subsequently, diagnostic tests of prolactin, thyroid hormones, follicle-stimulating hormone, and luteinizing hormone should be conducted to determine if the menstrual dysfunction is a result of endocrine pathologies such as (1) pituitary tumors, (2) adrenal diseases, (3) thyroid dysfunction, (4) polycystic ovarian syndrome (PCOS), (5) ovarian tumors, (6) gonadotropin mutations, (7) premature ovarian failure, and (8) hypothalamic causes [1, 9]. Hyperprolactinemia, as evidenced by high levels of prolactin, may indicate the presence of a prolactinoma in the pituitary, Atrophy and abnormal levels of thyroid-stimulating hormone or thyroxine may indicate thyroid diseases such as hyper- or hypothyroidism. Elevated follicle-stimulating hormone (FSH) levels are indicative of premature ovarian failure; whereas, an abnormally high LH/FSH ratio is often observed among women with PCOS [1, 3]. If physical symptoms of hyperandrogenism (hirsutism, acne, androgenic alopecia) are observed during the physical exam, serum androgens should also be assessed [9]. In the case of functional hypothalamic amenorrhea, prolactin, thyroid hormones, and androgens will be in the normal range; however, gonadotropins (LH and FSH) may be low or normal [1]. Low levels of estradiol may also be used to corroborate hypothalamic causes of amenorrhea [3]. For a detailed algorithm describing the steps involved in identifying the cause and diagnosing amenorrhea, please refer to the following book chapter referenced here [9]. A [Atot] The total concentration of weak acid (and bases) in solution. ATP Major energy and signaling molecule in living cells. Cross-References ▶ Adenosine Triphosphate Atrial fibrillation References 1. 2. 3. 4. 5. 6. 7. 8. 9. ASRM Practice Committee (2008) Current evaluation of amenorrhea. Fertil Steril 90(Suppl 1):S219–S225 De Souza MJ, Williams NI (2004) Physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism in exercising women. Hum Reprod Update 10(5):433–448 Nattiv A et al (2007) American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc 39(10):1867–1882 De Souza MJ et al (2007) Severity of energy-related menstrual disturbances increases in proportion to indices of energy conservation in exercising women. Fertil Steril 88(4):971–975 Loucks AB, Thuma JR (2003) Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab 88(1):297–311 Williams NI et al (2001) Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training: abrupt transition to exercise-induced amenorrhea. Endocrinology 142(6):2381–2389 Williams NI et al (2001) Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. J Clin Endocrinol Metab 86(11):5184–5193 De Souza MJ, Williams NI (2005) Beyond hypoestrogenism in amenorrheic athletes: energy deficiency as a contributing factor for bone loss. Curr Sports Med Rep 4(1):38–44 De Souza MJ, Toombs RJ (2010) Amenorrhea associated with the female athlete triad: etiology, diagnosis and treatment. In: Santoro NF, Neal-Perry G (eds) Amenorrhea: a case-based, clinical guide. Springer, New York, pp 101–125 Athletic Heart Syndrome ▶ Athlete’s Heart It’s an irregular and often rapid heart rate that commonly causes poor blood flow to the body. During atrial fibrillation the heart’s upper chambers (the atria) fibrillate, to be more precise they beat chaotically and irregularly, out of coordination with the two lower chambers of the heart (the ventricles). The blood is not pumped efficiently to the rest of the body which may cause shortness of breath, weakness and heart palpitation. Atrioventricular Node A localized area of the heart electrically connecting the atria to the ventricles which serves to delay the electrical signal to allow the cardiac atria to contract before the ventricles. The atria act as a primer pump for the larger ventricles. Atrophy The decrease in the size of an organ (e.g., muscle). This decrease is achieved by a decrease in the size of the cells by decreasing (i.e., cross sectional area) the components (e.g., contractile proteins) of the cell. In reference to skeletal muscle, a reduction in muscle or wasting of skeletal muscle which can result from disuse, aging, malnutrition, or disease such as muscular dystrophy. 111 A 112 A Automatic Implantable Cardioverter Defibrillator (AICD) Automatic Implantable Cardioverter Defibrillator (AICD) ▶ Implantable Cardioverter Defibrillator Autophagy A process where damaged cellular constituents, including organelles, are targeted for elimination through an energydependent process. Axon The axon is an anatomical component of the neuron that transmits an action potential to other neurons, or to muscle fibers.