Osteoporos Int (2010) 21:543–559

DOI 10.1007/s00198-009-1059-y

REVIEW

Sarcopenia: etiology, clinical consequences, intervention,

and assessment
T. Lang & T. Streeper & P. Cawthon & K. Baldwin &
D. R. Taaffe & T. B. Harris

Received: 25 April 2009 / Accepted: 18 August 2009 / Published online: 25 September 2009
# The Author(s) 2009. This article is published with open access at Springerlink.com

Abstract The aging process is associated with loss of muscle increased expression of inflammatory factors and other agents
mass and strength and decline in physical functioning. The which contribute to skeletal muscle catabolism. At the cellular
term sarcopenia is primarily defined as low level of muscle level, these molecular processes are manifested in a loss of
mass resulting from age-related muscle loss, but its definition muscle fiber cross-sectional area, loss of innervation, and
is often broadened to include the underlying cellular processes adaptive changes in the proportions of slow and fast motor
involved in skeletal muscle loss as well as their clinical units in muscle tissue. Ultimately, these alterations translate to
manifestations. The underlying cellular changes involve bulk changes in muscle mass, strength, and function which
weakening of factors promoting muscle anabolism and lead to reduced physical performance, disability, increased
risk of fall-related injury, and, often, frailty. In this review, we
T. Lang (*) summarize current understanding of the mechanisms under-
Department of Radiology and Biomedical Imaging, UCSF/UCB lying sarcopenia and age-related changes in muscle tissue
Joint Bioengineering Graduate Group, University of California, morphology and function. We also discuss the resulting long-
UCSF/Center for Molecular and Functional Imaging,
185 Berry Street, Suite 350,
term outcomes in terms of loss of function, which causes
San Francisco, CA 94143-0946, USA increased risk of musculoskeletal injuries and other morbid-
e-mail: [email protected] ities, leading to frailty and loss of independence.
T. Streeper
Department of Radiology and Biomedical Imaging,
Keywords Aging . Falls . Imaging . Muscle strength .
University of California, Sarcopenia . Skeletal muscle
UCSF/Center for Molecular and Functional Imaging,
185 Berry Street, Suite 350,
San Francisco, CA 94143-0946, USA
Introduction
P. Cawthon
California Pacific Medical Center Research Institute, Skeletal muscle contractions power human body move-
San Francisco, CA, USA ments and are essential to maintaining stability. Skeletal
K. Baldwin
muscle tissue accounts for almost half of the human body
Physiology and Biophysics, University of California, mass and, in addition to its power generation role, is a
Irvine, CA, USA crucial factor in maintaining homeostasis of glucose
metabolism. Given its central role in human mobility and
D. R. Taaffe
School of Human Movement Studies,
metabolic function, any deterioration in the contractile,
The University of Queensland, material, and metabolic properties of skeletal muscle has an
Brisbane, Australia extremely important effect on human health. Because the
population in the USA aged 65 and over is expected to
T. B. Harris
Laboratory of Epidemiology and Biometry,
approximately double over the next 15 years [1], age-
Intramural Research Program, National Institute on Aging, related losses in skeletal muscle mass and function present
Bethesda, MD, USA an extremely important current and future public health
544 Osteoporos Int (2010) 21:543–559

issue. Loss of mobility, one of the major consequences of between the motor neuron branch and the fiber, acetylcho-
age-related skeletal muscle deterioration, is one of the line is released from the axon end of the neuron. A wave of
primary determinants of the need for nursing home care, a electrical changes are produced in the muscle cell when the
public health cost which the US Health Care Finance acetylcholine binds to receptors on the fiber cell surface,
Administration predicts may exceed 183 million dollars by causing release of calcium from the sarcoplasmic reticulum,
2010 [2]. The term coined by I.H. Rosenberg, which is which activates the contractile machinery to generate
widely used to describe skeletal muscle loss, is sarcopenia, power.
from the Greek roots sarx (flesh) and penia (loss). The power generated in a muscle contraction is provided
Although this term is clinically applied to denote loss of by the interaction of the actin and myosin components
muscle mass, it is often used to describe both a set of within the sarcomere. In the broadest terms, this occurs
cellular processes (denervation, mitochondrial dysfunction, when the myosin component attaches to the actin frame-
inflammatory and hormonal changes) and a set of outcomes work. Following a sequence of chemical transformations
such as decreased muscle strength, decreased mobility and via actin-induced breakdown of adenosine triphosphate
function, increased fatigue, increased risk of metabolic (ATP), free energy is released to generate both force
disorders, and increased risk of falls and skeletal fractures. production and movement of actin within the sarcomere,
In this review, we (1) summarize current understanding of thereby causing the whole muscle to generate force and
the mechanisms which underlie sarcopenia, (2) relate this movement. Several reviews describing this process are
information to age-related changes in muscle tissue mor- provided in the following references [5–12].
phology and function, and (3) describe the resulting long- Motor units are differentiated into three main types
term outcomes in terms of loss of function, which cause based on the specific type of myosin expressed in the
increased risk of musculoskeletal injuries and other morbid- fibers. Slow motor units contain the smallest number of
ities, finally leading to frailty and loss of independence. fibers and consist of type 1 myosin, which transduces
energy at a relatively slow rate. Thus, these fibers/motor
units contract with relatively slow velocity. Type I fibers in
Muscle fiber structure and the neuromuscular junction slow motor units are especially rich in mitochondria and
myoglobin, which make them reddish in color and which
This section is derived from a number of excellent reviews allow for a high capacity for sustained delivery of ATP
of muscle cell structure and function [3, 4]. All of the from oxidative metabolism of triglycerides and carbohy-
body’s skeletal muscles are composed of multinucleated drate. The oxidative ATP synthesis process characteristic of
cells called fibers. Each fiber incorporates the contractile type I fibers is relatively slow to ramp up and can be
proteins myosin and actin, along with numerous other sustained for long periods of time, making these motors
regulatory proteins, which are organized into thick and thin units well-suited for sustained aerobic exercise such as
filaments, respectively. The myosin and actin filaments are distance running. Additionally, the low contraction velocity
arranged in periodic bands within structures called sarco- means that these slow motor units are also heavily recruited
meres, and a repeated sequence of sarcomeres form tube- in precise finite motor activities and in opposing gravity.
like structures called myofibrils. Each muscle fiber contains Fast fatigable motor units generate more force and have
a large number of parallel myofibrils, and the force higher velocities than slow motor units, both because they
generated by the muscle fiber is proportional to the number have the highest number of fibers and because the
of myofibrils it contains. Muscles are innervated by motor individual fibers have the largest cross-sectional area
neurons. In the case of small muscles used for fine motor (CSA) and the highest contractile velocity. These motor
control, motor neurons may innervate only a few small units express type IIx myosin, which transduces energy at a
fibers. In larger muscles, a fiber is innervated by a single faster rate than type I myosin. These fibers are relatively
branch of a motor neuron, and the motor neuron innervates poor in mitochondria, and the primary source of ATP is
many muscle fibers. The combination of a single motor through glycolysis of glycogen, which can provide consid-
neuron and the muscle fibers innervated by its branches is erable energy over a relatively short time period. Fast
called a motor unit. The hierarchic organization of muscle fatigable motor units are typically recruited during activities
tissue is diagrammed in Fig. 1. such as weightlifting or sprinting, which require maximal
A skeletal muscle motor unit is activated when a signal power generation. In addition, there is a third type of motor
is generated in the motor cortex of the brain, traveling unit, the fast fatigue-resistant motor unit, which transduces
though the spinal cord, and is transmitted as an action energy at a rate which is intermediate between slow and fast
potential through the motor neurons to each fiber in the fatigable motor units. Fast fatigue-resistant motor units
motor unit, resulting in a simultaneous contraction of the contain type IIa myosin and are intermediate in CSA
fibers. When the nerve impulse reaches the junction between type I and type IIx and are also intermediate in
Osteoporos Int (2010) 21:543–559 545

Fig. 1 Hierarchical depiction of skeletal muscle structure, depicting the skeletal muscle fibers within the muscle bundle, a motor unit branching
out to two muscle fibers and the detailed structure of myofibrils

terms of the number of fibers and in velocity of contraction. denervation, an increased burden of work is transferred to
Contractile force, normalized by CSA, is similar across surviving motor units, and as a potential adaptive response,
fiber types, but the maximum power, normalized for fiber remaining motor units recruit denervated fibers, changing
CSA, of the fast fatigable motor units is at least four times their fiber type to that of the motor unit. Thus, there is a net
greater due to the higher contractile velocity compared to conversion of type II fibers to type I fibers, as the type II
the slow type I motor units. fibers are recruited into slow motor units (Fig. 2). As a
result, although there is relatively little change in the
average CSA of type I fibers, the percentage of the total
Age-related changes in muscle contractile properties muscle cross-sectional area occupied by type I fibers tends
to increase with age, whereas not only are type II fibers lost
The term “sarcopenia” has been employed to describe the but the CSA and the aggregate power-generating capacity
loss of muscle tissue that occurs over a lifetime and is also of the remaining fibers also decrease dramatically. Finally,
commonly used to describe its clinical manifestation as while in young muscle tissue there is a mosaic-like
well. Age-associated processes bring about changes in the appearance corresponding to presence of both types of
mass, composition, contractile properties, and material fibers, in aged muscle, the recruitment of denervated fibers
properties of muscle tissue, as well as in the function of by surviving motor units causes a clustering of similar fiber
tendons. These changes translate to alterations in muscle types [13, 14].
power, strength, and function, leading to reduced physical The loss of both type I and accelerated loss of type II
performance, disability, increased risk of fall-related injury, fibers results in sharp age-related changes in muscle
and, often, frailty. This section will provide a brief review function. The loss of fast motor units and the concomitant
of some of the age-related changes that affect the contractile loss of type II fibers result in loss in muscle power
and material properties of muscle as well as the function of necessary for actions such as rising from a chair, climbing
tendons. steps, or regaining posture after a perturbation of balance.
The extent of skeletal muscle power loss with age has been
Age-related changes in muscle morphology confirmed by studies of cycle ergometry in which the cycle
velocity at maximal power was measured. In a study of
The age-related loss of muscle mass results from loss of human volunteers ranging in age from 20 to 90 years,
both slow and fast motor units, with an accelerated loss of Kostka et al. found that velocity at maximal power
fast motor units. In addition to the loss of fast motor units, decreased by roughly 18% between ages 20–29 and 50–
there appears to be fiber atrophy, or loss of CSA, of type II 59 and by a further 20% between 60–69 and 80–89 [15]. In
fast glycolytic fibers [13, 14]. As motor units are lost via addition to studies examining muscle power and contrac-
546 Osteoporos Int (2010) 21:543–559

Fig. 2 Effect of age on the

motor unit, depicting, young,
aged, and aged sarcopenic
fibers. This drawing depicts the
pronounced denervation of type
II fibers and the recruitment of
type I fibers into surviving mo-
tor units in older subjects, with
impairment of recruitment in
sarcopenic subjects

tion velocities, other studies have cross-sectionally exam- structure, including loss of muscle fibers, atrophy of muscle
ined age-related changes in strength, showing strength fibers, and increased clustering of muscle fibers as
declines as great as 30–35% [16]. These alterations in denervated fibers are recruited into viable motor units.
strength have been linked primarily to declines in muscle Multiple levels of the nervous system are affected by age,
mass as well as reductions in power per unit area and force including the motor cortex (beyond the scope of this
per unit area, as nonmuscle tissue components replace lost review), the spinal cord, peripheral neurons, and the
muscle fiber [17]. neuromuscular junction. Within the spinal cord, there is a
Another morphologic aspect of aging skeletal muscle is substantial decline in the number of alpha motor neurons,
the infiltration of muscle tissue components by lipid, which and there may be a preferential loss in those motor neurons
can be contained within adipocytes as well as deposited supplying fast motor units. Other reports have noted age-
within muscle fiber. The aging process is thought to result related losses in peripheral nerve fibers and alterations of
in increased frequency of adipocytes within muscle tissue. their myelin sheaths. Finally, age-related changes have been
As with precursor cells in bone marrow, liver, and kidney, noted in the neuromuscular junction, with reduced number
muscle satellite cells can express both adipocytic and a [30] but increased size of terminal areas and a reduction in
myocytic phenotypes, and recent studies have reported that the number of synaptic vesicles [31]. Others have noted
expression of the adipocytic phenotype is increased with increases in the amount of neurotransmitters released in
age [18–21]. This process is still relatively poorly under- nerve impulses and increased sprouting and branching of
stood in terms of its extent and spatial distribution. Another terminal axons, all of which may serve as an adaptive
well-known source of adiposity in muscle tissue is through mechanism underlying the ability of viable motor units to
increased deposition of lipid within muscle fibers [22–28]. recruit denervated muscle fibers [32].
This type of lipid distribution, often referred to as intra-
myocellular lipid, may result from net buildup of lipid due Key factors in age-related changes in protein balance
to reduced oxidative capacity of muscle fibers with aging
[22, 29]. Skeletal muscle is characterized by a dynamic balance
between the synthesis of protein from free amino acids in
Neurologic underpinnings of muscle atrophy the cellular milieu and the dissociation of muscle protein into
free amino acids. Maintenance of muscle mass requires that
The correct functioning of motor neurons is essential to the the rate of synthesis be in balance with the rate of degradation;
survival of muscle fibers. Age-related neurodegeneration over time, deficits can result in severe muscle loss. Aging is
may contribute importantly to the effects of age on muscle associated with decreased expression of hormonal factors that
Osteoporos Int (2010) 21:543–559 547

promote protein synthesis and increased expression of both synthesis and muscle cell function. Finally, loss of IGF-1
endocrine and inflammatory factors that contribute negatively may also compromise motor neuron function in aging. IGF-
to protein balance by increasing protein degradation. Figure 3 1 overexpression in transgenic mice has been reported to
summarizes the role of endocrine, inflammatory, and other protect against age-related changes in the neuromuscular
factors in protein synthesis. junction [38], and in other reports IGF-1 was found to be
instrumental in transforming nerve action potential to the
IGF-1 release of calcium ion from the sarcoplasmic reticulum
[39].
Insulin-like growth factor 1 (IGF-1) is a well-known
promoter of protein synthesis in skeletal muscle. Skeletal Age-related changes in inflammatory factors
muscle fibers have a set of transmembrane receptors that
bind insulin and IGF-1 to regulate proliferation, differenti- In chronic inflammatory diseases associated with muscle
ation, and fusion of skeletal muscle precursor cells [33]. atrophy, such as cancer cachexia and autoimmune disor-
There are two primary sources of IGF-1. Mature IGF-1 is ders, muscle cell protein degradation is accelerated, and
produced systemically by the interaction of growth hor- muscle protein synthesis appears to be diminished [40, 41].
mone (GH) with the liver. The other source of IGF-1 is The ubiquitin–proteasome pathway is the most important
within the skeletal muscle itself, with two primary variants mechanism for protein degradation in skeletal muscle cells.
[34], including one which is produced in response to This system involves a series of enzymatic steps in which
physical activity and is referred to as mechano growth the degraded proteins are first targeted by an enzyme
factor and one which is similar to the mature IGF-1 system that binds the target protein to the polypeptide
produced within the liver [35, 36]. IGF-1 binds to receptors ubiquitin. These ubiquitinized proteins are then transferred
on skeletal muscle cell surfaces and activates a complex to the proteasome complex and degraded into short peptides
array of cell signaling pathways which are anabolic, and are finally recycled as free intracellular amino acids
anticatabolic, and antiapoptotic [37]. This age-related [42]. This pathway is promoted by inflammatory cytokines
decline stems both from the decline of growth hormone, such as tumor necrosis factor alpha (TNF-α) and interleu-
which results in reduced liver IGF-1 production as well as a kin 6 (IL-6), by hormones such as cortisol and angiotensin,
reduction in the ability of skeletal muscle cells to produce as well as by reactive oxygen species.
IGF-1 locally. Therefore, the age-related decline in IGF-1 Increased expression of these inflammatory cytokines
production is linked to age-related reductions in protein also appears to be common in aging in skeletal muscle.

Fig. 3 Age effects on systemic

factors influencing synthesis and
degradation of skeletal muscle
proteins
548 Osteoporos Int (2010) 21:543–559

Comparison of skeletal muscle biopsies from younger and expression of MRFs such as myogenic determination factor
older subjects showed increased expression of genes (myoD), myogenic regulatory factor 5, and myogenin in
upregulated by inflammatory factors [43]. Levels of rats have found that expression of these factors is decreased
catabolism-inducing hormones such as cortisol have also in older compared to younger skeletal muscle [51]. Human
been shown to increase with age, and cortisol is linked to studies have shown impaired differentiation of myoblasts,
increased expression of IL-6 and TNF-α. Increased TNF-α which has been associated with reduced or delayed
expression is also known to stimulate muscle atrophy expression of these factors [52]. Another factor in the
through apoptosis. Apoptosis contributes to the loss of behavior of muscle satellite cells is myostatin, which is
myonuclei in skeletal muscle cells and could theoretically thought to suppress differentiation and proliferation of
result in the loss of complete fibers in sarcopenia [44]. myocytes by suppressing the expression of MRFs such as
myoD and myogenin [53]. While there is considerable
Oxidative damage work which has demonstrated that myostatin suppression
may have therapeutic potential for combating muscle
Oxidative metabolism generates reactive oxygen species wasting, the effect of age on myostatin expression is still
(ROS), and these metabolic products are thought to under active investigation. Some investigations using rat
accumulate over time, altering and damaging cell compo- models have found that myostatin mRNA levels have
nents, particularly mitochondria and DNA sequences [45]. remained constant with age [54], while others observed
Because mitochondria produce ROS, they are subject to age-related increases [55]. With respect to studies in human
alterations in their structure and in their DNA. Alterations models of muscle wasting, there is similar variance in
to mtDNA are known to increase with age in skeletal findings, with one cross-sectional study reporting no
muscle, and the frequency of abnormal mitochondrial change in myostatin expression in the vastus lateralis
regions is higher in those muscles which are strongly muscle between young and older men [56], while a similar
affected by sarcopenia [45–47]. The role of mitochondrial study in women found a 56% increase in myostatin
DNA alterations in age-related loss of skeletal muscle expression in the vastus lateralis [57]. Thus, while
function is under intense investigation, focusing on their myostatin is an important target in combating muscle
roles in causing skeletal muscle cell apoptosis and structural wasting, the role of age-related changes in myostatin
abnormalities that affect metabolic function. Structural expression is still a controversial subject.
alterations to mitochondria may affect the electron transport
chain, compromising respiration. Although the loss of
maximal oxygen consumption (VO2 max) with age has Age-related changes in the stiffness
been primarily attributed to loss of muscle mass and of the muscle–tendon system
reduced cardiac output, altered mitochondrial metabolism,
leading to poorer muscle cell respiration, may also be When considering age-related losses in performance, it is
involved. important to take into account that muscle and tendons act
as a unit. Human motion requires the transmission of
Intrinsic changes to skeletal muscle contractile forces generated in skeletal muscle tissue
through the tendons to the skeleton. Thus, age-related
One potential mechanism for sarcopenia involves the loss alterations in mobility are not only a function of changing
of muscle regenerative capacity due to loss in the number skeletal muscle contractile properties but also of the
and function of muscle satellite cells, which proliferate and mechanical properties of the tendons which operate in
differentiate into skeletal muscle fibers. Some studies have series with the muscle. A loss in tendon stiffness with age,
observed declines in the numbers of muscle satellite cells in for example, would reduce the rate of force development
both rodents and humans [48], with others reporting that caused by skeletal muscle contraction, whereas increased
this decline was larger in muscles containing primarily type tendon stiffness with age would tend to counteract the age-
II fibers than in those containing type 1 fibers [49]. related decrease in skeletal muscle contractile function.
However, other studies have failed to observe a change in Animal studies of age effects on tendon mechanical
satellite cell number with age, and others have even properties have yielded variable results, with some studies
reported slight increases [50]. There is some evidence that showing increased stiffness with age [58], while other
failure of muscle tissue to regenerate may involve age- studies have shown decreased stiffness with age [59, 60] or
related changes in the molecular regulators, called myo- little to no effect of age on tendon stiffness [61]. Narici et
genic regulatory factors (MRF) of muscle satellite cell al. have pointed out that some of this variability may be
proliferation and differentiation, rather than in the number attributable to differences in the age range between animal
of satellite cells. In general, studies that have compared the groups as well as due to measurement artifacts associated
Osteoporos Int (2010) 21:543–559 549

with clamping of the excised tendons [62]. Human studies can be isotonic, changing the length of the muscle fibers
of tendon properties have until recently been hindered by against constant resistance, isokinetic, in which fibers are
requirements for cadaver donors and have been somewhat shortened or lengthened at fixed velocity, or isometric, in
scarce. To study tendon properties in vivo, a technique has which fiber length remains constant in the presence of a
been developed based on longitudinal measurement of force greater than the muscle is capable of counteracting.
tendon deformation by imaging ultrasound during an Isokinetic and isotonic measurements of knee extension and
isometric muscle contraction [63]. Initial studies using this flexion, in that they involve translating a weight along an
technique compared young and elderly groups, observing arc of motion within a given time interval, are measures of
that tendons from older subjects were on the order of 15% muscle power (although they are mostly reported as joint
more compliant [62]. The observation that the tendons from torques in feet pounds or Newton meters) whereas
the young and older subjects had approximately similar isometric measurements involve purely the ability to
dimensions supported the idea that the observed differences generate force. Because these loading conditions are more
could be attributed to differences in mechanical properties. In relevant to human motion, most studies have reported
addition to the observation that older tendons have lower results of isokinetic and isotonic exercise. Table 1 summa-
stiffness than tendons from younger subjects, there is also rizes results of cross-sectional studies of lower-extremity
evidence that tendon stiffness can be increased through exercise muscle function [68–73]. In cross-sectional studies com-
training [64]. The ability to increase the stiffness of tendons paring young normal subjects in the 20–40-year age range
would improve mobility by allowing for faster generation of to healthy elders in the 70–80-year age range, declines in
force on bone, reducing the power and metabolic requirements knee extensor torque and power have ranged from 20% to
on skeletal muscle tissue. Narici et al. have presented excellent 40%, with greater losses in the 50% range reported for
reviews of the literature on age-related changes in human individuals in their 1990s [74–78]. Over the lifetime, men
tendon mechanical properties [62, 65]. have inherently greater knee extensor power and torque
than women, but on a percentage basis, age-related losses
are similar between genders, with losses in men incurring
Clinical manifestations of sarcopenia greater absolute losses because they start with higher
baseline values. Compared to the abundance of cross-
With aging, multiple processes occurring within muscle sectional studies, there are fewer longitudinal studies of
tissue, such as denervation, changes in the hormonal and knee extensor properties with aging. Hughes et al.
inflammatory environment, mitochondrial dysfunction, and examined a cohort of 52 elderly men and 68 women who
changes in the expression of regulatory factors affecting the had been examined 10 years earlier, finding similar declines
fate of satellite cells, combine to produce losses in the bulk in the knee extensors and flexors ranging from 12% to 18%
properties of muscle tissue such as muscle mass and per decade [79]. Longitudinal studies of smaller cohorts
strength. Among the elderly, these changes may eventually have shown variable results, with one study reporting losses
result in loss of mobility and independence and increased of roughly 3% per year in 23 men aged 73–86 at baseline
risk of injury. [80], and another study which reported no changes in
strength of either men or women over an 8-year follow-up
Loss of muscle power [81]. Cross-sectional studies of isometric measurements of
ankle plantar flexion have shown age-related declines
Age-related loss of skeletal muscle contractile power, similar to those measured for knee extension torque and
which is essential to human motions such as rising from a power. Studies of age-related muscle strength in the upper
chair or climbing a flight of stairs, is one of the clinical extremities show essentially similar results to the lower
consequences most commonly linked with sarcopenia. The extremities, with cross-sectional studies reporting declines
decline in muscle power has been established in both of 20–40% in measures such as hand-grip strength and
genders, under multiple loading conditions, in multiple elbow extension torque between healthy younger subjects
limbs, and in both cross-sectional and longitudinal studies and elderly subjects and longitudinal studies showing
[17]. The most important anatomic sites for muscle function yearly declines ranging from 1% to 5% [17].
measurement have primarily been in the lower body, as the
muscles in these sites are critical for daily function and Loss of skeletal muscle mass
allow for closest comparison to biopsy data. Further, power
and strength losses in the lower limbs confer the largest risk Loss of skeletal muscle mass with age has been docu-
factors for falls and other sources of injury and disability mented by lean body mass measurements with dual X-ray
[66, 67]. Lower-limb power and strength are often absorptiometry (DXA) and with muscle cross-sectional
measured using knee extension and flexion. Measurements areas quantified by three-dimensional imaging methods
550 Osteoporos Int (2010) 21:543–559

Table 1 Age-related changes in muscle power and muscle strength

Study Gender Measurement/joint/movement Age range (years) Study design Changes with aginga

Dean et al. 2004 [73] F IK/hip/FLX, EXT 21–82 CS ↓22–33%

Johnson et al. 2004 [72] F IK, IM/hip/AD, AB 21–91 CS ↓24–34% IK, ↓44–56% IM
Kubo et al. 2007 [71] M IM/ankle/PF 20–77 CS ↓40%
Morse et al. 2005 [70] M IM/ankle/PF 25.3±3.5–73.8±3.5 CS ↓47%
Petrella et al. 2005 [69] M, F IT/knee/EXT 20–75 CS ↓41–137%
Lanza et al. 2003 [68] M IT, IM/knee, ankle/EXT, DF 20–85 CS ↓26–32%

K isokinetic, IM isometric, IT isotonic, FLX flexion, EXT extension, AD adduction, AB abduction, PF plantar flexion; DF dorsiflexion, CS cross-
sectional
a
Expressed as percent change with aging

such as X-ray computed tomography (CT) or with magnetic Clearly, lower-extremity weakness is a better predictor of
resonance imaging (MRI). Leg lean tissue mass by DXA, a falls than weakness of the upper body. Other studies have
marker for skeletal muscle mass, decreases by roughly 1% explored the mechanisms by which impaired muscle
per year in longitudinal studies [17], a value roughly strength relates to falls by analyzing the effect of muscle
threefold smaller than the loss of skeletal muscle strength. strength in single-step recovery from a forward fall [84–
Studies which assess muscle mass through CSA measure- 87]. This may be simulated by leaning subjects forward and
ment have found that CSA decreases by roughly 40% then releasing them, measuring muscle activation, joint
between 20 and 60 years, with the reported amount varying kinetics, and other characteristics as the subjects step
with imaging technique, skeletal site, and gender [9, 16]. forward after release. Multiple studies have found that
Measurements of the CSA of the quadriceps muscle using older individuals have discernible differences in these
CT have shown decrements of around 25–35% between measurements. Thelen et al. compared muscle activities in
older subjects and young normal controls [82]. Large cross- young and elderly subjects and found that the latter showed
sectional studies including both older men and women have delays in activating the hip flexors and knee extensors
found that men, on average, have larger muscle mass and during the period in which the stepping leg is swung into
cross-sectional area values than women but that the largest position [84, 85]. Wojcik et al. found that elderly adults
cross-sectional age-related changes occurred in men. This generate lower hip flexion and extension torques than
potential gender difference in age-related loss of muscle young adults during single-step recoveries after being
mass may reflect differences in the pattern of age-related placed at a forward lean angle [86, 87]. Thus, there is
changes in testosterone, growth hormone, and IGF-1 [17]. evidence that reduced strength of the hip and other lower-
leg muscles, in addition to impaired neuromuscular activa-
Risk factors conferred by decrements in muscle power tion, may be implicated in poor recovery from falls. In
and mass addition to falls, muscle weakness and reduced muscle
mass have been associated with incident disability. The
Prospective cohort studies have demonstrated the associa- Health, Aging, and Body Composition Study investigators
tion of age-related loss of muscle strength and mass with carried out studies of body composition, muscle strength,
adverse clinical outcomes in the older population, including and other risk factors on incident mobility limitation,
falls, mobility limitations, incident disability, and fractures defined as inability to walk a quarter mile or climb a flight
[66, 67, 83]. Moreland et al. have carried out a meta- of ten stairs. Visser et al. observed that low-thigh muscle
analysis summarizing the relation of upper- and lower-body CSA measured at baseline resulted in a 45% and 34%
weakness to falls [67]. Measures of lower-body weakness, increased risk of mobility limitations 5 years later in men
defined as increased chair stand time and reduced knee and women, respectively [88]. For low-knee extensor
extension strength, have been correlated to incidence of any power and torque, the risk of incident mobility limitation
fall with odds ratios ranging from 1.2 to 2.5, to injurious was even higher, at 66% and 69% for men and women,
falls with odds ratios around 1.5, and to recurrent falls with respectively [88]. The same study found that men and
much higher odds ratios, ranging from 2.2 to 9.9. Upper- women in the lowest quartile of thigh muscle cross-
body weakness, which is typically assessed using hand-grip sectional area and leg muscle mass had a 30–40% increase
strength or manual muscle testing, is also correlated to fall of risk for the inability to carry out the activities of daily
incidence, with odds ratios for incident falls ranging from living. For major disability, which includes inability to
1.2 to 2.3 and for recurrent falls with odds ratios of 1.4–1.7. carry out activities of daily living, inability to walk a
Osteoporos Int (2010) 21:543–559 551

quarter mile, or climb ten steps, low-thigh CSA increased related muscle loss by increasing the number and cross-
risk by 40% whereas low-knee extensor strength resulted in sectional areas of skeletal muscle fibers. Increases of 11.4%
over a doubling of the risk. These subjects were also in midthigh muscle CSA and greater than 100% in knee
followed up for incident hospitalizations, and low-thigh extensor torque were reported by Frontera et al. in a cohort
CSA and muscle strength showed a similar predictive of elderly men who had undergone 12 weeks of high-
power for this outcome. Thigh muscle cross-sectional area intensity resistance exercise training [90], with similar
and knee extension torque have also been shown to changes observed in a subsequent study in women by
correlate to incident hip fracture in the Health ABC study Charette and colleagues [91]. Moreover, resistance exercise
[89]. Lang et al. observed that knee extension torque and even has benefits when it is not routinely performed. A
low cross-sectional area individually resulted in increased recent study by Henwood and Taaffe documented that
risk of incident hip fracture by 50–60%, independent of resistive exercise can produce sustained increases in knee
bone mineral density (BMD). extensor torque even after periods of deconditioning
The increased risk of mobility loss and injury resulting following cessation of exercise [92]. The benefits of
from loss of muscle mass and power are part of a vicious resistive exercise have been shown to extend even to frail
cycle which is amplified with age. In addition to reductions populations. Increases of 3–9% in muscle CSA, doubling of
in performance, the intermediate consequences of muscle muscle strength, and improvement in functional perfor-
loss include reductions in metabolic rate and aerobic mance indices have been reported in nursing home
capacity. The loss of power and endurance increase the populations after bouts of progressive resistance training
difficulties associated with procuring adequate nutrition and [93, 94]. Resistive exercise has been shown to be well
increase the effort required to undertake exercise. The tolerated in the elderly and is of value in the prevention of
combination of nutritional loss and reduced physical falls and loss of mobility. The time and equipment require-
activity levels results in further loss of muscle mass and ments to undertake a program of resistive exercise are
power, exacerbating the process of sarcopenia. The result- modest, with sessions of 30 min, twice per week, using
ing decrements in power, endurance, and physical perfor- either exercise machines or body weight and elastic bands.
mance, if unchecked, then lead to a loss of independence Finally, resistive exercise has been shown to result in
which may or may not be preceded by injury or illness, for improvement in a range of different clinical conditions
example a fall and/or fracture. common in elderly people, including osteoporosis, osteoar-
thritis, heart disease, diabetes, and depression. A summary
of relevant literature on exercise and pharmacologic
Treatments for sarcopenia intervention in the elderly is presented in Table 2.

Exercise Hormone replacement

Many studies have documented that exercise provides In elderly men, epidemiologic studies generally support a
benefits extending across multiple physiological systems relationship between declines in testosterone levels with age
in the aged population. Resistive training, also known as and loss of muscle strength and functional status [95].
weight or strength training, can be used to counteract age- Menopause and age-related reduction of estrogen levels in

Table 2 Studies examining various interventions for age-related muscle loss

Study Population Gender Age N Intervention Findings

Solerte et al. (2008) [149] S M, F 66–84 41 AA supp. ↑Lean mass, ↑IGF-1, ↓TNF-α
Trappe et al. (2000) [150] E M 74±2 7 RT ↑S; ↑MHC I
Trappe et al. (2001) [151] E F 74±2 7 RT ↑S
Slivka et al. (2008) [152] E M 80–86 6 RT ↑S, ↑CSA
Fiatarone et al. (1990) [93] E M 90±3 10 HIRT ↑S, ↑CSA
Kryger et al. (2007) [153] E M, F 85–97 11 RT ↑S, ↑CSA
Frontera et al. (2003) [154] E F 68–79 14 RT ↑S, ↑CSA
Wittert et al. (2003) [155] E M 60–86 76 TE ↔S, ↑CSA

S sarcopenia, E elderly, Myo-29 a myostatin inhibiting drug, AA Supp amino acid supplement, RT resistance training, HIRT high-intensity
resistance training, TE testosterone, S strength, CSA muscle cross-sectional area, IGF-1 insulin-like growth factor 1, TNF-α tumor necrosis factor
alpha, MHC I, myosin heavy chain type I isoform
552 Osteoporos Int (2010) 21:543–559

women may also impact muscle strength because estrogen the differentiation and proliferation of myocytes. In animal
is converted to testosterone, which has an anabolic effect on studies, myostatin blockade using experimental agents and
muscle protein synthesis. Further, both sex hormones may other approaches appears to produce increases in muscle
suppress inflammatory cytokines that exert catabolic effects mass and strength in rodent models [103–105]. Another
on muscle. Thus, hormone replacement has always received approach involves administration of selective androgen
considerable interest as a therapy for sarcopenia. In women, receptor modulators (SARMs). These nonsteroidal agents
trials of estrogen and testosterone therapy have failed to target the androgen receptor, which is found in sexual
yield any meaningful increases of muscle strength [96]. organs, skeletal muscle, and bone but have less of a
Studies of testosterone replacement therapy in men has had stimulative effect on prostate and other sexual organs,
mixed results, depending on age of the subjects. Several making them a candidate for treatment of frailty in older
studies have shown that administration of testosterone in subjects. These agents have been shown to improve lean
hypogonadal younger men produced significant increases body mass in rodent models [106] and are currently in early
in lean body mass and muscle strength [97–99]. Strength clinical trials.
increases ranged from 20% to 60% but tended to be smaller
than the increases produced by resistive exercise training. Skeletal muscle and bone strength
Anabolic effects of testosterone therapy on older hypogo-
nadal men tend to be weaker, with most studies reporting Maintenance of muscle mass and strength is critical for
minimal changes in body composition and no increases in preservation of physical activity in older age and important
muscle strength [96]. However, some studies have reported for reducing the risks of falls and their most serious
moderate strength improvements ranging from 10% to consequence, skeletal fractures. However, muscles exert
25%, but unlike the negative results, all of these trials powerful loads on the skeleton, and there is considerable
lacked control groups. However, it should be noted that interest in reducing fracture risk by using exercise strategies
testosterone is administered to older men in much lower to increase or at least protect against loss of skeletal mass
doses than to younger men because of increased risk of and strength with age [107]. The use of exercise strategies
prostate cancer and other side effects [96]. to strengthen the skeleton is based on the adaptive response
Considerable interest has also been devoted to testing the of bone to varying mechanical loads as described by Frost,
effect of GH on sarcopenia. Growth hormone exerts an who proposed a homeostatic process governing the balance
indirect anabolic effect on muscle by stimulating produc- between bone remodeling, modeling, and repair as a
tion of IGF-1 in the liver. Levels of growth hormone are function of varying strains imposed by inputs such as
systematically lower in the elderly, and thus it was impacts and muscle forces [108]. The relationship between
hypothesized that GH would be effective in combating mechanical strains and skeletal tissue responses vary with
muscle loss in elderly subjects. However, most studies have the skeletal site, but the “set points” that trigger remodeling
shown that GH treatment is ineffective in the elderly, both and modeling responses and thus the overall responsiveness
from the standpoint of muscle mass and muscle strength. of bone tissue to mechanical loading are modulated by the
The failure of GH treatment to augment muscle strength in overall hormonal milieu.
elderly subjects has led to other approaches, such as A series of animal experiments have studied the relation-
treatment with growth-hormone-releasing hormone, which ships between mechanical strain and bone geometry and
was found to increase GH production and produce moderate strength [109]. These studies have demonstrated the
increases in muscle strength [96–100]. Additionally, others responsiveness of skeletal tissue to dynamic changes in
have tried direct administration of IGF-1. By complexing mechanical loading and have shown the importance of the
IGF-1 to its primary circulating binding protein IGFBP-3, it timing as well as the magnitudes of applied loads [110].
is possible to significantly increase the IGF-1 dose while Recent studies have also indicated that mechanical loading has
eliminating the side effect of hypoglycemia that occurs with an effect on other properties of bone such as fatigue resistance
IGF-1 alone [101]. Boonen et al. reported that administration and second moment of inertia that are significantly larger than
of IGF-1/IGFBP-3 to elderly women with recent hip fracture effects on bone density and mass [111].
was well tolerated and resulted in increased grip strength However, studies examining the effect of exercise
[102]. regimes on bone in elderly subjects have indicated
relatively modest effects. An excellent review of various
Newer pharmacologic approaches exercise strategies on bone health has been published by
Suominen [107]. Impact exercise such as walking and
Among the newer approaches evolving towards treatment aerobic training has a pronounced benefit on overall health,
of muscle wasting is inhibition of myostatin, which and a small but positive effect on bone mass. However,
counteracts the myogenic regulatory factors which promote from an anabolic point of view, resistive exercise seems to
Osteoporos Int (2010) 21:543–559 553

exert more favorable effects for potential improvements of or to a bony landmark [23, 83, 88, 117–121]. As shown in
bone strength. High-intensity and progressive trials of Fig. 4, the key variables quantified include the total muscle
resistance exercise have shown significant effects on CSA of the midthigh, the CSA values of the quadriceps and
BMD at vertebral and hip sites. Studies in general have hamstrings, the total CSA of subcutaneous fat, and the
shown that the exercise must be continued to maintain the attenuation coefficients of the total thigh muscle and the
benefit that the additional gain is lost within a few years of hamstrings and quadriceps separately. The CSA values of
the program if the protocol is not continued. the total thigh muscle and quadriceps muscle are positively
associated with increasing knee extensor strength [118].
The CSA declines with age, as does the muscle strength,
Assessment of skeletal muscle using imaging and is smaller in females than in males [117–119]. Another
property of great interest to the study of sarcopenia is the
Imaging offers the potential for an anatomic site-specific mean attenuation coefficient [23, 117–119], which is
assessment of multiple targets related to skeletal muscle computed within all of the muscle regions after a threshold
physiology. Imaging has an important role in research is applied to exclude depots of fat embedded within each
studies of sarcopenia etiology and response to intervention. muscle group. In elderly subjects, the mean attenuation
The primary imaging target in skeletal muscle mass coefficient, when calculated in this manner, has been shown
assessment is lean body mass assessment by DXA, which histologically to correspond to fat accumulation within and
involves use of standard clinical bone densitometers to between the muscle cells. The increasing fat infiltration into
decompose nonbone tissue into lean and fat body mass the muscle with aging may be an important, if not central,
components. Measurements may be obtained of total body aspect of sarcopenia. Lower values of the mean thigh muscle
lean and fat mass as well as regional measures in the central attenuation coefficient correspond to increasing fattiness of
and appendicular skeleton. As this is an extremely muscle tissue. Decreasing thigh muscle attenuation is
widespread and well-known technology, which is commonly correlated to decreasing muscle strength, a relationship
used in clinical studies in both bone and muscle research, we which is independent of the muscle CSA and the total
will refer the readers to several reviews that lay out the amount of adipose tissue in the thigh.
technical considerations for DXA soft tissue assessment Measures of CSA and muscle attenuation assessed at
[112–116]. multiple skeletal sites are associated with indices of
CT imaging may be employed to quantify bulk charac- functional capacity in elderly adults, including chair stand
teristics of muscle and body composition that are highly and leg strength measurements which have been shown to
related to muscle strength and to overall functional ability be strongly predictive of falls [83, 88, 121]. Several studies
in the elderly. In particular, CT imaging is widely used to based on the Health, Aging, and Body Composition Study,
study muscle and fat in epidemiologic studies of body a large NIH-funded population study, have related measures
composition. Typically, acquisitions have included single of body composition derived by CT to indices of functional
cross sections at the L1/2 or L4/5 intervertebral space to ability and quality of life in the independently living
image body fat or volumetric measurements obtained in the elderly. Visser et al. examined the relationship between
abdomen and in the thigh, usually relating to the midthigh measures of thigh composition and lower-extremity perfor-

Fig. 4 CT acquisition through

midthigh. Location of axial sec-
tion is shown on localizer image
at the left, with corresponding
axial image in the middle and
segmentation into distinct tissue
compartments at the right.
Green: subcutaneous fat. Olive:
quadriceps muscle. Yellow:
hamstrings muscle. Red:
adductor muscles. Orange:
sartorius muscle
554 Osteoporos Int (2010) 21:543–559

mance (LEP), assessed by two timed tests: a series of five range of applications, the true advantage of MRI is the
chair stands without use of arms and a 6-m walk [83]. ability to obtain spectroscopic data that can probe in vivo
Reduced thigh CSA was associated with poorer LEP, as was the ATP-generating functions within skeletal muscle and
reduced thigh muscle attenuation coefficient, even after the the storage of important nutrients such as lipid and
adjustment for muscle area. The attenuation coefficient of glycogen.
thigh muscle is not only related to current physical Proton magnetic resonance spectroscopy (1H-MRS) is a
performance but is also related to incident functional technique that can differentiate lipids stored within adipo-
decline. Analyzing longitudinal data from the Health ABC cytes (extramyocellular lipid, EMCL) from intramyocellu-
study, Visser et al. observed that low baseline values of lar lipid (IMCL) stored as droplets on the border of the
thigh muscle attenuation predicted incident mobility limi- myoplasm [122–127]. This differentiation is based on the
tation, defined as inability to walk one-quarter mile or variance in resonance frequency between protons contained
climb ten steps [88]. Reduced thigh muscle attenuation in relatively cylindrical deposits of EMCL in adipocytes
coefficient is also associated with increased insulin resis- and protons contained in IMCL deposits which are
tance and the presence of metabolic syndrome in the spherical in shape. These resonances show up as different
elderly. Diabetes and other weight-related health conditions peaks on the proton spectrum of skeletal muscle (Fig. 5).
are associated with poor vision, musculoskeletal pain, and Probing IMCL is of clinical importance because IMCL
other conditions which are themselves indicators of stores represent lipid which borders mitochondria and
increased fall risk [23]. which represent an energy supply of free fatty acids for
oxidation. IMCL intensity determined by 1H-MRS has been
Magnetic resonance imaging found to correlate with insulin resistance and obesity. The
risk of insulin resistance is known to increase with age, and
MRI is an imaging technique that is based on using radio aging skeletal muscle is characterized by decreasing
waves to excite protons in the presence of an external oxidative capacity that may lead to increased IMCL.
magnetic field. The resonance frequency at which protons MRS may also be used to detect resonances of 31P and
13
maximally absorb the radioenergy is based on their local C nuclei contained in ATP, ADP inorganic phosphate,
chemical environment. Because musculoskeletal tissues are glycogen, and other chemical forms in skeletal muscle
rich in proton-containing molecules such as muscle proteins cells, shedding important light on muscle metabolism. 31P-
and lipids, MRI is an inherently powerful tool at depicting MRS can be used to directly analyze relative abundances of
31
the anatomy of muscle tissues, particularly in the delinea- P contained in compounds of interest to energetics of
tion of lean and adipose components of muscles. While skeletal muscle, including ATP, inorganic phosphate, and
some investigators have used 3D MRI acquisitions to phosphocreatine [128–134]. Based on these primary meas-
determine lean tissue and intermuscular fat volumes in a urements, it is also possible to use 31P-MRS to indirectly

Fig. 5 MRI image of calf at the right, with green and yellow boxes extramyocellular lipid. At the right, a proton spectrum corresponding
indicating locations of spectroscopic acquisitions of the tibialis to the soleus muscle shows 1H resonances associated with creatinine
anterior and soleus muscles, respectively. Proton spectroscopy studies (CR2 and CR3), water, extramyocellular lipid (EMCL), intramyocel-
may be used to assess the relative amounts of intramyocellular and lular lipid (IMCL), and trimethylamines (TMA)
Osteoporos Int (2010) 21:543–559 555

estimate the intracellular pH, as well as the free concen- Conclusions

trations of ADP and Mg2+ ions. These measurements allow
the technique to be used to estimate rates of ATP synthesis Sarcopenia represents a set of outcomes, including the
under ischemic (glycogenolytic) conditions or aerobic primary outcomes of loss of skeletal muscle strength and
(oxidative) conditions. Other applications in skeletal muscle endurance, and secondary outcomes which include loss of
studies include estimates of the oxidative capacity of mobility and increased risk of disability and mortality. The
skeletal muscle, as well as the proton efflux and buffer bulk changes of muscle tissue which lead to these outcomes
capacity, which provide insight into the recovery of skeletal result from multiple processes occurring at the cellular
muscle from exercise. level. These processes impact the performance of muscle by
The wide chemical shift of the 13C resonance allows reducing the number of fibers and the performance of
13
C-MRS to assess the relative abundances of a wide range individual fibers. Age-related loss of motor neurons results
of molecules related to glycogen synthesis and glycogen- in denervation of entire fibers, with a concomitant adaptive
olysis [129, 135–143]. Using the natural abundance (1.1%) process that recruits some but not all of these of these fibers
of 13C, it is possible to detect resonances of 13C in glycogen into surviving motor units. Changes in the hormonal and
and triglyceride. This allows for estimates of glycogen inflammatory milieu result in impairment of protein
turnover in skeletal muscle and for studies of insulin synthesis and increased protein degradation. Buildup or
resistance and type 2 diabetes. By administration of 13C ROS may result in mitochondrial dysfunction which
glucose, it is possible to enrich 13C, allowing for more impairs muscle respiration and may result in fiber deterio-
advanced determinations, such as examining glycogen ration through loss of myonuclei. Alterations in expression
synthesis rate and quantifying organelle and mitochondrial of myogenic regulatory factors may impair the ability of
activity during the TCA cycle. aged muscle to repair damage. Fortunately, despite this
wide range of deleterious age-related changes, there are
Positron emission tomography promising interventions. Multiple studies have shown that
resistive exercise among the elderly of both genders can
Positron emission tomography (PET) is an imaging result in substantial improvements in muscle strength and in
technique which is employed to image the biodistribution overall functional status, where increases in muscle strength
of a compound of interest labeled with a positron-emitting indices can exceed 50–100%. For subjects who cannot
atom, for example an 18F or 11C. The most commonly tolerate or are unwilling to undertake exercise, pharmaco-
employed PET imaging agent is 18F-fluorodeoxyglucose logic interventions, such as GH or IGF-1 interventions, are
(FDG), a glucose analog which is widely employed to under investigation. These have had mixed results, and
study glucose metabolism across multiple tissue types. 18F- newer approaches, such as myostatin inhibition and
FDG penetrates the cell membrane and is phosphorylated to selective androgen receptor modulators, are also in the
FDG-6-phosphate and is no longer metabolized and thus is early stages of investigation. Noninvasive imaging
trapped within the cell. It builds up in the cell in proportion approaches such as CT, MRI, and PET are showing promise
to the rate of glucose transport across the cell membrane as clinical tools that may yield important basic information
and also in relation to the activities of hexokinase and regarding the mechanisms of sarcopenia and the modes of
glucose-6-phospotase within the cell. In skeletal muscle, action of multiple interventions.
FDG imaging has been employed to study glucose
utilization. When used in conjunction with compartmental Conflicts of interest Thomas Lang has received an Independent
modeling, this approach has been employed to dissect the Investigator Grant from Merck.
rate of glucose utilization in terms of the components of cell
Open Access This article is distributed under the terms of the
membrane transport and phosphorylative activity in insulin
Creative Commons Attribution Noncommercial License which per-
resistance associated with both obesity and diabetes [144, mits any noncommercial use, distribution, and reproduction in any
145]. Another application of PET which is relevant to medium, provided the original author(s) and source are credited.
skeletal muscle is the use of 11C-methyl-methionine to
estimate the rate of protein synthesis. This agent accumu-
lates in skeletal muscle as 11C-labeled protein, and the use References
of this methylated agent has advantages over radiolabeled
leucine in that the latter accumulates in the blood as 11C- 1. Bureau UC (2006) In: Bureau UC (ed) US Census Bureau:
labeled CO2. Fischmann and others have validated this international database. Table 94.
2. Greenlund LJ, Nair KS (2003) Sarcopenia—consequences, mech-
technique against skeletal muscle biopsy and have used it to
anisms, and potential therapies. Mech Ageing Dev 124:287–299
outline the rate of skeletal muscle protein synthesis in 3. Brooks SV (2003) Current topics for teaching skeletal muscle
healthy young volunteers [146–148]. physiology. Adv Physiol Educ 27:171–182
556 Osteoporos Int (2010) 21:543–559

4. Faulkner JA, Larkin LM, Claflin DR, Brooks SV (2007) Age- 27. Kelley DE, Goodpaster BH, Storlien L (2002) Muscle triglycer-
related changes in the structure and function of skeletal muscles. ide and insulin resistance. Annu Rev Nutr 22:325–346
Clin Exp Pharmacol Physiol 34:1091–1096 28. Kraegen EW, Cooney GJ (2008) Free fatty acids and skeletal
5. Brooks SV, Faulkner JA (1994) Skeletal muscle weakness in muscle insulin resistance. Curr Opin Lipidol 19:235–241
old age: underlying mechanisms. Med Sci Sports Exerc 26: 29. Hamilton MT, Areiqat E, Hamilton DG, Bey L (2001) Plasma
432–439 triglyceride metabolism in humans and rats during aging and
6. Celichowski J (2000) Mechanisms underlying the regulation of physical inactivity. Int J Sport Nutr Exerc Metab 11(Suppl):S97–
motor unit contraction in the skeletal muscle. J Physiol Pharmacol 104
51:17–33 30. Ramirez V, Ulfhake B (1992) Anatomy of dendrites in
7. Herzog W, Ait-Haddou R (2002) Considerations on muscle motoneurons supplying the intrinsic muscles of the foot sole in
contraction. J Electromyogr Kinesiol 12:425–433 the aged cat: evidence for dendritic growth and neo-
8. Larsson L, Ramamurthy B (2000) Aging-related changes in skeletal synaptogenesis. J Comp Neurol 316:1–16
muscle. Mechanisms and interventions. Drugs Aging 17:303–316 31. Kullberg S, Ramirez-Leon V, Johnson H, Ulfhake B (1998)
9. Porter MM, Vandervoort AA, Lexell J (1995) Aging of human Decreased axosomatic input to motoneurons and astrogliosis in
muscle: structure, function and adaptability. Scand J Med Sci the spinal cord of aged rats. J Gerontol Ser A Biol Sci Med Sci
Sports 5:129–142 53:B369–379
10. Sakamoto K, Goodyear LJ (2002) Invited review: intracellular 32. Gordon T, Hegedus J, Tam SL (2004) Adaptive and maladaptive
signaling in contracting skeletal muscle. J Appl Physiol motor axonal sprouting in aging and motoneuron disease. Neurol
93:369–383 Res 26:174–185
11. Westerblad H, Allen DG, Bruton JD, Andrade FH, Lannergren J 33. Florini JR, Ewton DZ, Falen SL, Van Wyk JJ (1986) Biphasic
(1998) Mechanisms underlying the reduction of isometric force concentration dependency of stimulation of myoblast differenti-
in skeletal muscle fatigue. Acta Physiol Scand 162:253–260 ation by somatomedins. Am J Physiol 250:C771–778
12. Wick M (1999) Filament assembly properties of the sarcomeric 34. Goldspink G, Yang SY (2004) The splicing of the IGF-I gene to
myosin heavy chain. Poult Sci 78:735–742 yield different muscle growth factors. Adv Genet 52:23–49
13. Lexell J, Downham DY (1991) The occurrence of fibre-type 35. Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G,
grouping in healthy human muscle: a quantitative study of cross- Molinaro M, Barton ER, Sweeney HL, Rosenthal N (2001)
sections of whole vastus lateralis from men between 15 and Localized Igf-1 transgene expression sustains hypertrophy and
83 years. Acta Neuropathol 81:377–381 regeneration in senescent skeletal muscle. Nat Genet 27:195–
14. Lexell J, Downham DY, Larsson Y, Bruhn E, Morsing B (1995) 200
Heavy-resistance training in older Scandinavian men and 36. Petrella JK, Kim JS, Cross JM, Kosek DJ, Bamman MM (2006)
women: short- and long-term effects on arm and leg muscles. Efficacy of myonuclear addition may explain differential
Scand J Med Sci Sports 5:329–341 myofiber growth among resistance-trained young and older
15. Kostka T (2005) Quadriceps maximal power and optimal men and women. Am J Physiol Endocrinol Metab 291:E937–
shortening velocity in 335 men aged 23–88 years. Eur J Appl 946
Physiol 95:140–145 37. Firth SM, Baxter RC (2002) Cellular actions of the insulin-like
16. Vandervoort AA (2002) Aging of the human neuromuscular growth factor binding proteins. Endocr Rev 23:824–854
system. Muscle Nerve 25:17–25 38. Messi ML, Delbono O (2003) Target-derived trophic effect on
17. Doherty TJ (2003) Invited review: aging and sarcopenia. J Appl skeletal muscle innervation in senescent mice. J Neurosci
Physiol 95:1717–1727 23:1351–1359
18. Kirkland JL, Tchkonia T, Pirtskhalava T, Han J, Karagiannides I 39. Schertzer JD, van der Poel C, Shavlakadze T, Grounds MD,
(2002) Adipogenesis and aging: does aging make fat go MAD? Lynch GS (2008) Muscle-specific overexpression of IGF-I
Exp Gerontol 37:757–767 improves E–C coupling in skeletal muscle fibers from dystrophic
19. Shefer G, Van de Mark DP, Richardson JB, Yablonka-Reuveni Z mdx mice. Am J Physiol Cell Physiol 294:C161–168
(2006) Satellite-cell pool size does matter: defining the myogenic 40. Rasmussen BB, Fujita S, Wolfe RR, Mittendorfer B, Roy M,
potency of aging skeletal muscle. Dev Biol 294:50–66 Rowe VL, Volpi E (2006) Insulin resistance of muscle protein
20. Shefer G, Wleklinski-Lee M, Yablonka-Reuveni Z (2004) metabolism in aging. FASEB J 20:768–769
Skeletal muscle satellite cells can spontaneously enter an 41. Kandarian SC, Jackman RW (2006) Intracellular signaling
alternative mesenchymal pathway. J Cell Sci 117:5393–5404 during skeletal muscle atrophy. Muscle Nerve 33:155–165
21. Shefer G, Yablonka-Reuveni Z (2007) Reflections on lineage 42. Reid MB (2005) Response of the ubiquitin–proteasome pathway
potential of skeletal muscle satellite cells: do they sometimes go to changes in muscle activity. Am J Physiol Regul Integr Comp
MAD? Crit Rev Eukaryot Gene Expr 17:13–29 Physiol 288:R1423–1431
22. Dube J, Goodpaster BH (2006) Assessment of intramuscular 43. Giresi PG, Stevenson EJ, Theilhaber J, Koncarevic A, Parkington J,
triglycerides: contribution to metabolic abnormalities. Curr Opin Fielding RA, Kandarian SC (2005) Identification of a molecular
Clin Nutr Metab Care 9:553–559 signature of sarcopenia. Physiol Genomics 21:253–263
23. Goodpaster BH, Brown NF (2005) Skeletal muscle lipid and its 44. Leeuwenburgh C (2003) Role of apoptosis in sarcopenia. J
association with insulin resistance: what is the role for exercise? Gerontol Ser A Biol Sci Med Sci 58:999–1001
Exerc Sport Sci Rev 33:150–154 45. Hiona A, Leeuwenburgh C (2008) The role of mitochondrial DNA
24. Goodpaster BH, Kelley DE (2002) Skeletal muscle triglyceride: mutations in aging and sarcopenia: implications for the mitochon-
marker or mediator of obesity-induced insulin resistance in type drial vicious cycle theory of aging. Exp Gerontol 43:24–33
2 diabetes mellitus? Curr Diab Rep 2:216–222 46. Dirks AJ, Hofer T, Marzetti E, Pahor M, Leeuwenburgh C
25. Johnson NA, Stannard SR, Thompson MW (2004) Muscle (2006) Mitochondrial DNA mutations, energy metabolism and
triglyceride and glycogen in endurance exercise: implications for apoptosis in aging muscle. Ageing Res Rev 5:179–195
performance. Sports Med 34:151–164 47. Herbst A, Pak JW, McKenzie D, Bua E, Bassiouni M, Aiken JM
26. Kelley DE (2002) Skeletal muscle triglycerides: an aspect of (2007) Accumulation of mitochondrial DNA deletion mutations
regional adiposity and insulin resistance. Ann N Y Acad Sci in aged muscle fibers: evidence for a causal role in muscle fiber
967:135–145 loss. J Gerontol Ser A Biol Sci Med Sci 62:235–245
Osteoporos Int (2010) 21:543–559 557

48. Conboy IM, Conboy MJ, Smythe GM, Rando TA (2003) Notch- 70. Morse CI, Thom JM, Reeves ND, Birch KM, Narici MV (2005) In
mediated restoration of regenerative potential to aged muscle. vivo physiological cross-sectional area and specific force are
Science 302:1575–1577 reduced in the gastrocnemius of elderly men. J Appl Physiol
49. Verdijk LB, Koopman R, Schaart G, Meijer K, Savelberg HH, 99:1050–1055
van Loon LJ (2007) Satellite cell content is specifically reduced 71. Kubo K, Morimoto M, Komuro T, Tsunoda N, Kanehisa H,
in type II skeletal muscle fibers in the elderly. Am J Physiol Fukunaga T (2007) Age-related differences in the properties of the
Endocrinol Metab 292:E151–157 plantar flexor muscles and tendons. Med Sci Sports Exerc 39:541–
50. Dreyer HC, Blanco CE, Sattler FR, Schroeder ET, Wiswell RA 547
(2006) Satellite cell numbers in young and older men 24 hours 72. Johnson ME, Mille ML, Martinez KM, Crombie G, Rogers MW
after eccentric exercise. Muscle Nerve 33:242–253 (2004) Age-related changes in hip abductor and adductor joint
51. Gallegly JC, Turesky NA, Strotman BA, Gurley CM, Peterson CA, torques. Arch Phys Med Rehabil 85:593–597
Dupont-Versteegden EE (2004) Satellite cell regulation of muscle 73. Dean JC, Kuo AD, Alexander NB (2004) Age-related changes in
mass is altered at old age. J Appl Physiol 97:1082–1090 maximal hip strength and movement speed. J Gerontol Ser A
52. Bigot A, Jacquemin V, Debacq-Chainiaux F, Butler-Browne GS, Biol Sci Med Sci 59:286–292
Toussaint O, Furling D, Mouly V (2008) Replicative aging 74. Larsson L, Grimby G, Karlsson J (1979) Muscle strength and
down-regulates the myogenic regulatory factors in human speed of movement in relation to age and muscle morphology. J
myoblasts. Biol Cell 100:189–199 Appl Physiol 46:451–456
53. McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R 75. Murray MP, Duthie EH Jr, Gambert SR, Sepic SB, Mollinger LA
(2003) Myostatin negatively regulates satellite cell activation and (1985) Age-related differences in knee muscle strength in normal
self-renewal. J Cell Biol 162:1135–1147 women. J Gerontol 40:275–280
54. Kawada S, Tachi C, Ishii N (2001) Content and localization of 76. Murray MP, Gardner GM, Mollinger LA, Sepic SB (1980)
myostatin in mouse skeletal muscles during aging, mechanical Strength of isometric and isokinetic contractions: knee muscles
unloading and reloading. J Muscle Res Cell Motil 22:627–633 of men aged 20 to 86. Phys Ther 60:412–419
55. Baumann AP, Ibebunjo C, Grasser WA, Paralkar VM (2003) 77. Young A, Stokes M, Crowe M (1984) Size and strength of the
Myostatin expression in age and denervation-induced skeletal quadriceps muscles of old and young women. Eur J Clin Invest
muscle atrophy. J Musculoskelet Neuronal Interact 3:8–16 14:282–287
56. Welle S (2002) Cellular and molecular basis of age-related 78. Young A, Stokes M, Crowe M (1985) The size and strength of
sarcopenia. Can J Appl Physiol 27:19–41 the quadriceps muscles of old and young men. Clin Physiol
57. Raue U, Slivka D, Jemiolo B, Hollon C, Trappe S (2006) 5:145–154
Myogenic gene expression at rest and after a bout of resistance 79. Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE,
exercise in young (18–30 yr) and old (80–89 yr) women. J Appl Roubenoff R, Fiatarone Singh MA (2001) Longitudinal muscle
Physiol 101:53–59 strength changes in older adults: influence of muscle mass,
58. Shadwick RE (1990) Elastic energy storage in tendons: physical activity, and health. J Gerontol Ser A Biol Sci Med Sci
mechanical differences related to function and age. J Appl 56:B209–217
Physiol 68:1033–1040 80. Aniansson A, Hedberg M, Henning GB, Grimby G (1986)
59. Nakagawa Y, Hayashi K, Yamamoto N, Nagashima K (1996) Muscle morphology, enzymatic activity, and muscle strength in
Age-related changes in biomechanical properties of the Achilles elderly men: a follow-up study. Muscle Nerve 9:585–591
tendon in rabbits. Eur J Appl Physiol Occup Physiol 73:7–10 81. Greig CA, Botella J, Young A (1993) The quadriceps strength of
60. Blevins FT, Hecker AT, Bigler GT, Boland AL, Hayes WC healthy elderly people remeasured after eight years. Muscle
(1994) The effects of donor age and strain rate on the Nerve 16:6–10
biomechanical properties of bone–patellar tendon–bone allog- 82. Overend TJ, Cunningham DA, Paterson DH, Lefcoe MS (1992)
rafts. Am J Sports Med 22:328–333 Thigh composition in young and elderly men determined by
61. Flahiff CM, Brooks AT, Hollis JM, Vander Schilden JL, computed tomography. Clin Physiol 12:629–640
Nicholas RW (1995) Biomechanical analysis of patellar tendon 83. Visser M, Kritchevsky S, Goodpaster B, Newman A, Nevitt M,
allografts as a function of donor age. Am J Sports Med 23:354– Stamm E, Harris T (2002) Leg muscle mass and composition in
358 relation to lower extremity performance in men and women aged
62. Narici MV, Maffulli N, Maganaris CN (2008) Ageing of human 70–79: the health aging and body composition study. J Am
muscles and tendons. Disabil Rehabil 30:1548–1554 Geriat Soc 50:897–905
63. Maganaris CN, Paul JP (1999) In vivo human tendon mechanical 84. Thelen DG, Muriuki M, James J, Schultz AB, Ashton-Miller JA,
properties. J Physiol 521(Pt 1):307–313 Alexander NB (2000) Muscle activities used by young and old
64. Reeves ND, Narici MV, Maganaris CN (2003) Strength training adults when stepping to regain balance during a forward fall. J
alters the viscoelastic properties of tendons in elderly humans. Electromyogr Kinesiol 10:93–101
Muscle Nerve 28:74–81 85. Thelen DG, Wojcik LA, Schultz AB, Ashton-Miller JA,
65. Narici MV, Maganaris CN (2006) Adaptability of elderly human Alexander NB (1997) Age differences in using a rapid step to
muscles and tendons to increased loading. J Anat 208:433–443 regain balance during a forward fall. J Gerontol Ser A Biol Sci
66. Nevitt MC, Cummings SR, Kidd S, Black D (1989) Risk factors Med Sci 52:M8–13
for recurrent nonsyncopal falls. JAMA 261:2663–2668 86. Wojcik LA, Thelen DG, Schultz AB, Ashton-Miller JA,
67. Moreland JD, Richardson JA, Goldsmith CH, Clase CM (2004) Alexander NB (1999) Age and gender differences in single-
Muscle weakness and falls in older adults: a systematic review step recovery from a forward fall. J Gerontol Ser A Biol Sci Med
and meta-analysis. J Am Geriatr Soc 52:1121–1129 Sci 54:M44–50
68. Lanza IR, Towse TF, Caldwell GE, Wigmore DM, Kent-Braun 87. Wojcik LA, Thelen DG, Schultz AB, Ashton-Miller JA,
JA (2003) Effects of age on human muscle torque, velocity, and Alexander NB (2001) Age and gender differences in peak lower
power in two muscle groups. J Appl Physiol 95:2361–2369 extremity joint torques and ranges of motion used during single-
69. Petrella JK, Kim JS, Tuggle SC, Hall SR, Bamman MM (2005) step balance recovery from a forward fall. J Biomech 34:67–73
Age differences in knee extension power, contractile velocity, 88. Visser M, Goodpaster BH, Kritchevsky SB, Newman AB, Nevitt
and fatigability. J Appl Physiol 98:211–220 M, Rubin SM, Simonsick EM, Harris TB (2005) Muscle mass,
558 Osteoporos Int (2010) 21:543–559

muscle strength, and muscle fat infiltration as predictors of 106. Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller
incident mobility limitations in well-functioning older persons. J DD, Dalton JT (2005) Selective androgen receptor modulator
Gerontol Ser A Biol Sci Med Sci 60:324–333 treatment improves muscle strength and body composition and
89. Lang TF, Cauley J, Tylavsky F, Bauer D, Cummings S, Harris prevents bone loss in orchidectomized rats. Endocrinology
TB (2009) Computed tomography measurements of thigh muscle 146:4887–4897
cross-sectional area and attenuation coefficient predict hip 107. Suominen H (2006) Muscle training for bone strength. Aging
fracture: The Health, Aging and Body Composition Study. J Clin Exp Res 18:85–93
Bone Miner Res doi:10.1359/jbmr.090807 108. Frost HM (1987) Bone “mass” and the “mechanostat”: a
90. Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans proposal. Anat Rec 219:1–9
WJ (1988) Strength conditioning in older men: skeletal muscle 109. Bass SL, Saxon L, Daly RM, Turner CH, Robling AG, Seeman
hypertrophy and improved function. J Appl Physiol 64:1038–1044 E, Stuckey S (2002) The effect of mechanical loading on the size
91. Charette SL, McEvoy L, Pyka G, Snow-Harter C, Guido D, and shape of bone in pre-, peri-, and postpubertal girls: a study in
Wiswell RA, Marcus R (1991) Muscle hypertrophy response to tennis players. J Bone Miner Res 17:2274–2280
resistance training in older women. J Appl Physiol 70:1912– 110. Robling AG, Hinant FM, Burr DB, Turner CH (2002) Shorter,
1916 more frequent mechanical loading sessions enhance bone mass.
92. Henwood TR, Taaffe DR (2008) Detraining and retraining in Med Sci Sports Exerc 34:196–202
older adults following long-term muscle power or muscle 111. Warden SJ, Hurst JA, Sanders MS, Turner CH, Burr DB, Li J
strength specific training. J Gerontol A Biol Sci Med Sci (2005) Bone adaptation to a mechanical loading program
63:751–758 significantly increases skeletal fatigue resistance. J Bone Miner
93. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA, Res 20:809–816
Evans WJ (1990) High-intensity strength training in nonagenar- 112. Albanese CV, Diessel E, Genant HK (2003) Clinical applications
ians. Effects on skeletal muscle. JAMA 263:3029–3034 of body composition measurements using DXA. J Clin Densitom
94. Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR, 6:75–85
Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA, Evans WJ (1994) 113. Pichard C, Genton L, Jolliet P (2000) Measuring body
Exercise training and nutritional supplementation for physical composition: a landmark of quality control for nutritional
frailty in very elderly people. N Engl J Med 330:1769–1775 support services. Curr Opin Clin Nutr Metab Care 3:281–284
95. Morley JE, Haren MT, Kim MJ, Kevorkian R, Perry HM 3rd 114. Plank LD (2005) Dual-energy X-ray absorptiometry and body
(2005) Testosterone, aging and quality of life. J Endocrinol composition. Curr Opin Clin Nutr Metab Care 8:305–309
Invest 28:76–80 115. Wells JC, Fewtrell MS (2006) Measuring body composition.
96. Borst SE (2004) Interventions for sarcopenia and muscle Arch Dis Child 91:612–617
weakness in older people. Age Ageing 33:548–555 116. Woodrow G (2007) Body composition analysis techniques in
97. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, adult and pediatric patients: how reliable are they? How useful
Cunningham G, Matsumoto AM, Weber T, Berman N (2000) are they clinically? Perit Dial Int 27(Suppl 2):S245–249
Transdermal testosterone gel improves sexual function, mood, 117. Goodpaster BH, Carlson CL, Visser M, Kelley DE, Scherzinger
muscle strength, and body composition parameters in hypogo- A, Harris TB, Stamm E, Newman AB (2001) Attenuation of
nadal men. J Clin Endocrinol Metab 85:2839–2853 skeletal muscle and strength in the elderly: the health ABC study.
98. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, J Appl Physiol 90:2157–2165
Phillips J, Lee WP, Bunnell TJ, Casaburi R (1997) Testosterone 118. Goodpaster BH, Kelley DE, Thaete FL, He J, Ross R (2000)
replacement increases fat-free mass and muscle size in hypo- Skeletal muscle attenuation determined by computed tomogra-
gonadal men. J Clin Endocrinol Metab 82:407–413 phy is associated with skeletal muscle lipid content. J Appl
99. Brodsky IG, Balagopal P, Nair KS (1996) Effects of testosterone Physiol 89:104–110
replacement on muscle mass and muscle protein synthesis in 119. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M,
hypogonadal men—a clinical research center study. J Clin Schwartz AV, Simonsick EM, Tylavsky FA, Visser M, Newman
Endocrinol Metab 81:3469–3475 AB (2006) The loss of skeletal muscle strength, mass, and
100. Fuh VL, Bach MA (1998) Growth hormone secretagogues: quality in older adults: the health, aging and body composition
mechanism of action and use in aging. Growth Horm IGF Res study. J Gerontol Ser A Biol Sci Med Sci 61:1059–1064
8:13–20 120. Taaffe DR, Henwood TR, Nalls MA, Walker DG, Lang TF,
101. Giovannini S, Marzetti E, Borst SE, Leeuwenburgh C (2008) Harris TB (2008) Alterations in muscle attenuation following
Modulation of GH/IGF-1 axis: potential strategies to counteract detraining and retraining in resistance-trained older adults.
sarcopenia in older adults. Mech Ageing Dev 129:593–601 Gerontology 55:217–223
102. Boonen S, Rosen C, Bouillon R, Sommer A, McKay M, 121. Visser M, Deeg DJ, Lips P, Harris TB, Bouter LM (2000)
Rosen D, Adams S, Broos P, Lenaerts J, Raus J, Vander- Skeletal muscle mass and muscle strength in relation to lower-
schueren D, Geusens P (2002) Musculoskeletal effects of the extremity performance in older men and women. J Am Geriatr
recombinant human IGF-I/IGF binding protein-3 complex in Soc 48:381–386
osteoporotic patients with proximal femoral fracture: a double- 122. Boesch C, Machann J, Vermathen P, Schick F (2006) Role of
blind, placebo-controlled pilot study. J Clin Endocrinol Metab proton MR for the study of muscle lipid metabolism. NMR
87:1593–1599 Biomed 19:968–988
103. Bradley L, Yaworsky PJ, Walsh FS (2008) Myostatin as a 123. Machann J, Stefan N, Schick F (2008) (1)H MR spectroscopy of
therapeutic target for musculoskeletal disease. Cell Mol Life Sci skeletal muscle, liver and bone marrow. Eur J Radiol 67:275–284
65:2119–2124 124. Torriani M (2007) Measuring muscle lipids with 1H-MR
104. Tobin JF, Celeste AJ (2005) Myostatin, a negative regulator of spectroscopy. Skeletal Radiol 36:607–608
muscle mass: implications for muscle degenerative diseases. 125. Weis J, Courivaud F, Hansen MS, Johansson L, Ribe LR,
Curr Opin Pharmacol 5:328–332 Ahlstrom H (2005) Lipid content in the musculature of the lower
105. Walsh FS, Celeste AJ (2005) Myostatin: a modulator of skeletal- leg: evaluation with high-resolution spectroscopic imaging.
muscle stem cells. Biochem Soc Trans 33:1513–1517 Magn Reson Med 54:152–158
Osteoporos Int (2010) 21:543–559 559

126. Weis J, Johansson L, Ortiz-Nieto F, Ahlstrom H (2008) magnetic resonance spectroscopy in humans: effect of nutritional
Assessment of lipids in skeletal muscle by high-resolution solutions. MAGMA 11:114–121
spectroscopic imaging using fat as the internal standard: 142. Shulman RG, Rothman DL (2001) 13C NMR of intermediary
comparison with water referenced spectroscopy. Magn Reson metabolism: implications for systemic physiology. Annu Rev
Med 59:1259–1265 Physiol 63:15–48
127. Wells GD, Noseworthy MD, Hamilton J, Tarnopolski M, Tein I 143. Van Den Bergh AJ, Tack CJ, Van Den Boogert HJ, Vervoort G,
(2008) Skeletal muscle metabolic dysfunction in obesity and Smits P, Heerschap A (2000) Assessment of human muscle
metabolic syndrome. Can J Neurol Sci 35:31–40 glycogen synthesis and total glucose content by in vivo 13C
128. Bendahan D, Mattei JP, Guis S, Kozak-Ribbens G, Cozzone PJ MRS. Eur J Clin Invest 30:122–128
(2006) Non-invasive investigation of muscle function using 31P 144. Bertoldo A, Pencek RR, Azuma K, Price JC, Kelley C, Cobelli
magnetic resonance spectroscopy and 1H MR imaging. Rev C, Kelley DE (2006) Interactions between delivery, transport,
Neurol (Paris) 162:467–484 and phosphorylation of glucose in governing uptake into human
129. Boesch C (2007) Musculoskeletal spectroscopy. J Magn Reson skeletal muscle. Diabetes 55:3028–3037
Imaging 25:321–338 145. Bertoldo A, Price J, Mathis C, Mason S, Holt D, Kelley C,
130. Brosseau OE, Mahdjoub R, Seurin MJ, Thiriet P, Gozal D, Cobelli C, Kelley DE (2005) Quantitative assessment of glucose
Briguet A (2003) Kinetics of anaerobic metabolism in human transport in human skeletal muscle: dynamic positron emission
skeletal muscle: influence of repetitive high-intensity exercise on tomography imaging of [O-methyl-11C]3-O-methyl-D-glucose. J
sedentary dominant and non-dominant forearm. A 31P NMR Clin Endocrinol Metab 90:1752–1759
study. Biochimie 85:885–890 146. Carter EA, Yu YM, Alpert NM, Bonab AA, Tompkins RG,
131. Lanza IR, Befroy DE, Kent-Braun JA (2005) Age-related Fischman AJ (1999) Measurement of muscle protein synthesis
changes in ATP-producing pathways in human skeletal muscle by positron emission tomography with L-[methyl-11C]methio-
in vivo. J Appl Physiol 99:1736–1744 nine: effects of transamination and transmethylation. J Trauma
132. Lanza IR, Wigmore DM, Befroy DE, Kent-Braun JA (2006) In 47:341–345
vivo ATP production during free-flow and ischaemic muscle 147. Fischman AJ, Yu YM, Livni E, Babich JW, Young VR, Alpert NM,
contractions in humans. J Physiol 577:353–367 Tompkins RG (1998) Muscle protein synthesis by positron-
133. Mairiang E, Hanpanich P, Sriboonlue P (2004) In vivo 31P- emission tomography with L-[methyl-11C]methionine in adult
MRS assessment of muscle-pH, cytosolic-[Mg2+] and phos- humans. Proc Natl Acad Sci U S A 95:12793–12798
phorylation potential after supplementing hypokaliuric renal 148. Hsu H, Yu YM, Babich JW, Burke JF, Livni E, Tompkins RG,
stone patients with potassium and magnesium salts. Magn Young VR, Alpert NM, Fischman AJ (1996) Measurement of
Reson Imaging 22:715–719 muscle protein synthesis by positron emission tomography with
134. Taylor JH, Beilman GJ, Conroy MJ, Mulier KE, Myers D, L-[methyl-11C]methionine. Proc Natl Acad Sci U S A 93:1841–
Gruessner A, Hammer BE (2004) Tissue energetics as measured 1846
by nuclear magnetic resonance spectroscopy during hemorrhagic 149. Solerte SB, Gazzaruso C, Bonacasa R, Rondanelli M, Zamboni
shock. Shock 21:58–64 M, Basso C, Locatelli E, Schifino N, Giustina A, Fioravanti M
135. Delmas-Beauvieux MC, Quesson B, Thiaudiere E, Gallis JL, (2008) Nutritional supplements with oral amino acid mixtures
Canioni P, Gin H (1999) 13C nuclear magnetic resonance study increases whole-body lean mass and insulin sensitivity in elderly
of glycogen resynthesis in muscle after glycogen-depleting subjects with sarcopenia. Am J Cardiol 101:69E–77E
exercise in healthy men receiving an infusion of lipid emulsion. 150. Trappe S, Williamson D, Godard M, Porter D, Rowden G,
Diabetes 48:327–333 Costill D (2000) Effect of resistance training on single muscle
136. Hunter GR, Newcomer BR, Larson-Meyer DE, Bamman MM, fiber contractile function in older men. J Appl Physiol 89:143–
Weinsier RL (2001) Muscle metabolic economy is inversely 152
related to exercise intensity and type II myofiber distribution. 151. Trappe S, Godard M, Gallagher P, Carroll C, Rowden G, Porter
Muscle Nerve 24:654–661 D (2001) Resistance training improves single muscle fiber
137. Krssak M, Petersen KF, Bergeron R, Price T, Laurent D, Rothman contractile function in older women. Am J Physiol Cell Physiol
DL, Roden M, Shulman GI (2000) Intramuscular glycogen and 281:C398–406
intramyocellular lipid utilization during prolonged exercise and 152. Slivka D, Raue U, Hollon C, Minchev K, Trappe S (2008) Single
recovery in man: a 13C and 1H nuclear magnetic resonance muscle fiber adaptations to resistance training in old (>80 yr)
spectroscopy study. J Clin Endocrinol Metab 85:748–754 men: evidence for limited skeletal muscle plasticity. Am J
138. Meynial-Denis D, Miri A, Bielicki G, Mignon M, Renou JP, Physiol Regul Integr Comp Physiol 295:R273–280
Grizard J (2005) Insulin-dependent glycogen synthesis is delayed 153. Kryger AI, Andersen JL (2007) Resistance training in the
in onset in the skeletal muscle of food-deprived aged rats. J Nutr oldest old: consequences for muscle strength, fiber types,
Biochem 16:150–154 fiber size, and MHC isoforms. Scand J Med Sci Sports 17:
139. Rico-Sanz J, Zehnder M, Buchli R, Dambach M, Boutellier U 422–430
(1999) Muscle glycogen degradation during simulation of a 154. Frontera WR, Hughes VA, Krivickas LS, Kim SK, Foldvari M,
fatiguing soccer match in elite soccer players examined non- Roubenoff R (2003) Strength training in older women: early and
invasively by 13C-MRS. Med Sci Sports Exerc 31:1587–1593 late changes in whole muscle and single cells. Muscle Nerve
140. Rico-Sanz J, Zehnder M, Buchli R, Kuhne G, Boutellier U 28:601–608
(1999) Noninvasive measurement of muscle high-energy phos- 155. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P,
phates and glycogen concentrations in elite soccer players by Morley JE (2003) Oral testosterone supplementation increases
31
P- and 13C-MRS. Med Sci Sports Exerc 31:1580–1586 muscle and decreases fat mass in healthy elderly males with low-
141. Rotman S, Slotboom J, Kreis R, Boesch C, Jequier E (2000) normal gonadal status. J Gerontol Ser A Biol Sci Med Sci
Muscle glycogen recovery after exercise measured by 13C- 58:618–625