University of Dundee

Optimal management of sarcopenia

Burton, Louise A.; Sumukadas, Deepa

Published in:
Clinical Interventions in Aging

DOI:
10.2147/CIA.S11473

Publication date:
2010

Link to publication in Discovery Research Portal

Citation for published version (APA):

Burton, L. A., & Sumukadas, D. (2010). Optimal management of sarcopenia. Clinical Interventions in Aging, 5,
217-228. 10.2147/CIA.S11473

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Optimal management of sarcopenia

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Clinical Interventions in Aging
4 August 2010
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Louise A Burton Abstract: Sarcopenia is the progressive generalized loss of skeletal muscle mass, strength,
Deepa Sumukadas and function which occurs as a consequence of aging. With a growing older population, there
has been great interest in developing approaches to counteract the effects of sarcopenia, and
Ageing and Health, Division of Medical
Sciences, University of Dundee, thereby reduce the age-related decline and disability. This paper reviews (1) the mechanisms of
Dundee, Scotland, United Kingdom sarcopenia, (2) the diagnosis of sarcopenia, and (3) the potential interventions for ­sarcopenia.
Multiple factors appear to be involved in the development of sarcopenia including the loss of
muscle mass and muscle fibers, increased inflammation, altered hormonal levels, poor ­nutritional
status, and altered renin–angiotensin system. The lack of diagnostic criteria to identify patients
with sarcopenia hinders potential management options. To date, ­pharmacological ­interventions
have shown limited efficacy in counteracting the effects of sarcopenia. Recent evidence has shown
benefits with angiotensin-converting enzyme inhibitors; however, further randomized controlled
trials are required. Resistance training remains the most effective intervention for sarcopenia;
however, older people maybe unable or unwilling to embark on strenuous exercise training
programs.
Keywords: aged, muscle function, sarcopenia

Background
Maintaining muscle function is vital to maintain functional independence. In our
­growing older population, muscle mass and force reach their peak between the second
and fourth decades of life and thereafter show a steady decline with age.1 Sarcopenia is
a syndrome characterized by progressive generalized loss of skeletal muscle mass and
strength. It is usually accompanied by physical inactivity, decreased mobility, slow gait,
and poor physical endurance which are also common features of the frailty syndrome.2
Rockwood et al3 described the concept of frailty as “a multidimensional syndrome
which involves loss of reserves (energy, physical activity, cognition, and health) which
gives rise to increased vulnerability”. Frailty involves a cumulative decline in multiple
physiological systems including a decline in the neuromuscular system which is linked
to the development of sarcopenia in later life. The loss of muscle mass during the ­ageing
process is clinically important as it leads to reduced strength and exercise capacity,
both of which are required to undertake normal daily living activities. Moreover, loss
Correspondence: Deepa Sumukadas of muscle mass is a strong predictor of mortality in later life.4
Ageing and Health, Mailbox 1, Ninewells
Hospital and Medical School, Dundee
It has been estimated that up to 15% of people older than 65 years and as many as
DD1 9SY, Scotland, United Kingdom 50% of people older than 80 years have sarcopenia.5 Sarcopenia has a major impact
Tel +44 01382 632436
Fax +44 01382 660675
on public health and the cost in the united States alone was estimated at $18.5 ­billion
Email [email protected] in 2000.6 With the increasing number of older people worldwide, the cost is ever

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11473 article which permits unrestricted noncommercial use, provided the original work is properly cited.
Burton and Sumukadas Dovepress

i­ ncreasing. There has, therefore, been great interest in of skeletal muscle appear to decrease in old age. It has been
­developing approaches to counteract the effects of ­sarcopenia suggested that the renin–angiotensin system may play a role
and thereby help in reducing the age-related decline and in modulating muscle function. Circulating angiotensin 2
disability. is associated with muscle wasting, reduced IGF-1 levels,
and insulin resistance and could, therefore, contribute to
What causes sarcopenia? ­sarcopenia.10 Sarcopenia is also associated with chronic
Understanding the mechanisms that have been implicated inflammation, and observational studies have shown increased
in the development of sarcopenia can help direct sarcopenia levels of proinflammatory cytokines, tumor necrosis factor-α,
treatments. Research is still ongoing but as yet no primary and interleukin-6 in aging muscle.11 Studies looking at treat-
cause of sarcopenia has been identified. Multiple factors ing sarcopenia have attempted to address some of the factors
appear to be involved in the development of sarcopenia implicated in the development of sarcopenia and we discuss
­(Figure 1). A reduction in muscle strength is primarily linked the evidence surrounding this in our review.
to a reduction in overall muscle mass.7 This reduction in
muscle mass may occur due to a combination of the loss of Diagnosis of sarcopenia
muscle fibers as well as muscle fiber atrophy with a preferen- The first step in the management of sarcopenia is to diagnose
tial atrophy of type 2 fast twitch fibers. Denervation of motor the condition. Unfortunately, at present there are no standard-
units which is then reinnervated with slow motor units can ized diagnostic criteria for sarcopenia. Although sarcopenia is
lead to increased muscle fatigability.8 Although the overall considered as a dynamic process incorporating both changes
biological mechanism of sarcopenia is not fully understood, in muscle mass and function, many observational studies have
observational studies have shown that satellite cells which concentrated on assessing changes in muscle mass. Table 1 sum-
are involved in muscle regeneration are much lower in older marizes the measurement techniques, what they measure, and
people and, therefore, could play a role in sarcopenia.9 their limitations. Although magnetic resonance imaging (MRI)
Other factors including hormonal changes including is considered to be the most accurate measure of muscle mass,
growth hormone (GH) and insulin-like growth factor (IGF-1) the currently preferred method is dual energy X-ray absorpti-
and androgens which help regulate growth and development ometry (DXA) as it measures both fat mass and bone mass and

Other factors
↓ Motor units Nutrition
↓ No. muscle fibers ↓ Muscle mass Hormones
↑ Muscle fiber ↓ Muscle strength Metabolic
atrophy Immunological
RAAS

SARCOPENIA

↑ Weakness ↑ Disability

↑ Disability
Loss of independence

Figure 1 Mechanism of sarcopenia.

Abbreviation: RAAS, renin–angiotensin–aldosterone system.

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Dovepress Optimal management of sarcopenia

Table 1 Measuring techniques for sarcopenia

Measuring techniques Measurements Comments
Muscle size
CT Scan Muscle cross-sectional area Radiation exposure, expensive
MRI Scan Muscle cross-sectional area Expensive, availability of MRI
BIA Tissue conductivity ? reliability
Muscle circumferences Mid arm and calf circumference Measurements effected by subcutaneous fat
DXA scan Total skeletal muscle mass Reliable, low radiation exposure
Physical performance
SPPB Lower extremity function Validated tool for older people
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; BIA, bioelectric impedence analysis; DXA, dual energy X-ray absorptiometry; SPPB, Short
Physical Performance Battery.

is useful for assessing appendicular muscle mass. DXA closely Although this definition includes measures of ­functional
correlates with measurements achieved via MRI scanning.12 The performance and helps to eliminate variance between ­ethnicity
main limitation with DXA is that it may ­underestimate the extent and sex, it fails to set age-specific populations. It has been
of sarcopenia as it can overestimate skeletal muscle mass by as suggested that a T-score system similar to that for ­osteoporosis
much as 8% due to difficulty in distinguishing muscle from water is needed to include reference values for ­different populations.
retention and muscle fat ­infiltration.13 Bioelectric Impedence However, further refinement is required.
Analysis is a quick noninvasive method for ­measuring body The main effect of loss of muscle mass is loss of strength.
composition via tissue conductivity.14 However, its reliability has Low muscle strength is associated with increased mortality.18
been called into question as measurements can vary depending Although complex measures of power and torque are avail-
on an individual’s hydration status, ethnicity, physical ­fitness, able, hand-held dynamometers to measure hand grip and
and age.15 quadriceps strength have been commonly used with good
Baumgartner5 in 1998 proposed a method for ­diagnosing reproducibility and validity and are simple to use and can
sarcopenia. The degree of sarcopenia was measured by taking be easily used in the clinical setting.19
the muscle mass relative to a person’s height. ­Appendicular Physical performance measures can complement
skeletal mass (ASM) was measured in all four limbs with ­measures of muscle mass and strength in the diagnosis of
DXA. Individuals with ASM/height2 (kg/m2) of two stan- sarcopenia. The Short Physical Performance Battery assesses
dard deviations (SDs) below the mean for gender specific muscle function and strength using measures which are
healthy younger adults were more likely to have sarcopenia. reproducible to activities of daily living. The assessment
Janssen et al16 measured skeletal muscle mass using bioim- involves balance tests, a timed 4-meter walk, and timed chair
pedence and defined sarcopenia as a skeletal muscle index rise which can be easily performed in the clinical setting. It
(skeletal muscle mass/whole body mass × 100) less than 1 can predict the risk of future disability and, therefore, may
SD below the mean for young adult values. These defini- be useful in identifying people in the preclinical stage of
tions fail to incorporate measures of disability and physical sarcopenia who may benefit from interventions.20
performance.16 Comorbidities and factors like pain from osteoarthritis
Since then attempts have been made to refine the ­definition of which are unrelated to sarcopenia may limit performance and
sarcopenia. More recently, a joint effort has been made between underestimate muscle strength. Fat mass may contribute to
the European Society on Clinical ­Nutrition and Metabolism functional decline independent of muscle mass.21 Individuals
and the Special Interest Needs group on geriatric nutrition on with sarcopenic obesity (high fat mass and low muscle mass)
cachexia – anorexia and chronic ­wasting diseases.17 A diagnosis are more susceptible to mobility problems and disability than
of sarcopenia was based on two of the following: those who are simply obese or sarcopenic.22 It is, therefore,
i. A low muscle mass, ie, a percentage of muscle mass .2 imperative that sarcopenia is diagnosed under its paradigm as
SDs below the mean measured in groups of young adults a dynamic process by assessing lean body mass and physical
of the same sex and ethnic background. performance. As yet this may be more difficult to reproduce
ii. Low gait speed, ie, walking speed below 0.8 m/s in the in a clinical setting.
4-meter walking test. However, this could be replaced The main difficulties in diagnosing sarcopenia are the
with one well-established functional test utilized locally lack of consensus in the definition of sarcopenia as well
as part of a comprehensive geriatric assessment. as the difficulty in measuring changes in muscle mass and

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function over time in older people. In clinical practice, the likely to contribute to muscle hypertrophy, it can increase the
diagnosis is often missed as it is usually made in patients cross-sectional area (CSA) of muscle fibers.27 Mitochondrial
who appear to have “small muscle mass”. Simple measures volume and enzyme activity increase after aerobic exercise
of muscle strength and physical performance measures can demonstrate that muscle protein synthesis and muscle quality
supplement clinical diagnosis for the early recognition of improve irrespective of age.28 Aerobic exercise can also reduce
people at risk of disability. body fat including intramuscular fat which in turn improves
the functional role of muscle relative to body weight.29
Potential interventions In contrast to aerobic exercise training, resistance exercise
for sarcopenia training appears to have a larger effect on augmenting
Exercise and physical activity muscle mass and strength and attenuates the development
Physical activity refers to the body movement that is of sarcopenia.30,31 Improvements in muscle strength can be
­produced by skeletal muscle contractions and that increases achieved with as little as one resistance exercise training
energy expenditure.23 Evidence has shown that older adults session per week.32 Frontera et al33 demonstrated improve-
who are less physically active are more likely to have lower ments in muscle CSA by 11% as well as improvement in
skeletal muscle mass and strength and are at increased risk muscle strength (.100%) after a 12-week period of high
of developing sarcopenia.24,25 intensity resistance exercise training in older men. Similar
In aerobic exercise, the larger muscles in the body move improvements were seen in muscle strength even in the
in a rhythmic manner for a prolonged period of time, whereas people aged .90 years with as little as 10–12 weeks of
resistance exercise involves muscles working hard against an training.34
applied force or weight such as in weight-lifting. Both aerobic and Muscle hypertrophy occurs when muscle protein synthesis
resistance-type exercise training have shown to improve the rate outweighs protein breakdown. Older people performing resis-
of decline in muscle mass and strength with age (Table 2).26 tance exercise show a marked increase in skeletal muscle protein
Aerobic activity (swimming, running, and walking) has synthesis without an increase in whole body muscle breakdown.
long been linked to improvements in cardiovascular fitness Resistance training in older people increases both mixed-muscle
and endurance capacity. Although aerobic exercise is less protein synthesis and specific major ­histocompatibility complex

Table 2 Summary of treatment options

Intervention Effect Comments
Exercise Increased cardiovascular fitness with increased endurance Pros: overall beneficial effects
Aerobic Increases mitochondrial volume and activity of exercise to individual
Resistance Increased muscle mass and strength Cons: motivation
Increased skeletal muscle protein synthesis and muscle fiber size to exercise remains low
Improvement in physical performance
Nutritional supplement Varying evidence of increased muscle mass and strength Pros: ensures good protein intake
Cons: may reduce natural food intake
Hormone therapy Varying evidence of increased muscle mass and strength Cons: masculinization of women;
Testosterone increased risk of prostatic cancer in men
 Estrogen Poor evidence of increased muscle mass but not function Cons: risk of breast cancer
Growth hormone Some evidence for increased muscle mass. Varying evidence Cons: side effects including fluid
for increased muscle strength retention, orthostatic hypotension
Vitamin D Variable evidence for increased muscle Pros: fracture reduction; possible
strength cardiovascular benefits
Reduced falls in nursing home residents
ACE inhibitors Some evidence for increased exercise capacity Pros: other cardiovascular benefits
Cons: renal function needs monitoring
Creatine Variable evidence of increased muscle strength Cons: reports of nephritis
and endurance especially when combined with exercise
Potential new treatments
Myostatin antagonists No trials in older people
PPAR [δ] agonist No human trials
AICAR No human trials
Abbreviations: PPAR-δ, peroxisome-proliferator-activated receptor-δ; AICAR, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside; ACE, angiotensin-converting
enzyme.

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synthesis to the same levels as younger adults.35 Evidence points protein diet below the RDA leads to a significant decline in
to increases in size of both type 1 and type 2 muscle fibers muscle strength and muscle mass in older women.43 However,
which could explain the improvements in muscle strength and even older people who take the recommended RDA for protein
endurance.33,36 More recently, it has been reported that when using continue to have a negative nitrogen balance and may require a
moderate ­levels of resistance exercise training, improvements in diet containing a higher protein content than the RDA to main-
muscle strength and size in healthy older people were comparable tain their skeletal muscle.44 Protein and energy supplementa-
to muscle strength seen in younger individuals. Roth et al37 dem- tion may increase muscle strength even in very old people in
onstrated that 6 months of whole body resistance ­training in older the short term, but a Cochrane review has found no definite
people (65–75 years) produced gains in muscle CSA similar to functional benefit of nutritional supplementation.45–47
those achieved in younger individuals aged 20–30 years. Although older people who exercise have increased pro-
Progressive resistance training (PRT) is the most com- tein requirements, studies investigating whether nutritional
monly used resistance therapy in older people. A Cochrane supplementation in combination with resistance training can
review of 121 randomized controlled trials of PRT in older augment muscle strength gains in older people have yielded
people showed that doing PRT 2–3 times per week improved inconsistent results. One randomized controlled trial in
physical function, gait speed, timed get-up and go, climbing nursing home residents undergoing resistance training over
stairs and balance, and more importantly had a significant 10 weeks found that an additional 360 calories supplement
effect on muscle strength especially in the high intensity increased leg muscle strength.36 Another study investigating
training groups.38 the effect of dietary protein supplementation in combination
The majority of studies have shown that resistance with a 12-week resistance training period found that protein
­exercise training must be carried out at a high intensity supplementation increased muscle mass but not muscle
in order to show substantial improvements in muscle strength.48 Nutritional supplementation may also result in
strength.33,36,37 In contrast, Vincent et al39 performed a an overall decrease in voluntary food intake and adherence
26-week study in older healthy adults at both low and high to the supplements can be a problem.47
intensity resistance exercise training programs and found
only a modest improvement in thigh muscle strength in the Testosterone
high intensity resistance exercise training group. Testosterone is secreted by the Leydig cells in men and ovar-
Resistance exercise training appears to be relatively safe to ian thecal cells in women.49 Testosterone appears to increase
perform even in participants with multiple comorbidities and muscle mass and increase muscle protein synthesis.50 It also
can help in prevention of falls.40 Resistance exercise increases increases the number of satellite cells in both animals and
muscle CSA as well as type 2 (fast twitch) muscle fibers, which humans which are essential for muscle cell function.51
leads to overall improvement in muscle power and the ability A substantial number of older men are hypogonadal.
to improve physical functioning. As a result, this can lead to Hypogonadism has been defined as a total testosterone con-
enhanced ability to perform activities of daily living, preventing centration of ,9.26 nmol/L (2 SD below the mean for healthy
in functional decline and ­disability. Even in very old nursing young men). As a result, approximately 20% of men .60 years
home residents, resistance ­exercise ­training showed substantial and 50% men .80 years are ­categorized as hypogonadal.52 Cir-
improvements in muscle fiber CSA (3%–9%), muscle strength culating testosterone is highly bound to sex ­hormone binding
(.100%) as well as ­improvements in physical performance such globulin (SHBG) and as SHBG increases with age, the total
as gait speed and stair climbing.36,38 However, participation in amount of bioavailable ­testosterone decreases. This phenom-
regular exercise training requires motivation by the individual enon has been termed the “male menopause” or “andropause”
which may be difficult for some older individuals; therefore, in older men. ­Testosterone decreases gradually at a rate of
nonexercise interventions may offer a useful alternative. 1% per year and ­bioavailable testosterone by 2% per year in
males from the age of 30 years.53 The overall reduction of
Nutrition testosterone is associated with loss of muscle strength, muscle
Many older adults do not consume sufficient amounts of dietary mass, a reduction in bone mineral density, and increased risk
protein which leads to a reduction in lean body mass and of fracture risk following falls.54,55
increased functional impairment.41 The ­current ­recommended Evidence to support testosterone supplementation is
dietary allowance (RDA) of protein is 0.8 g/kg/day, almost 40% variable. Gruenewald and Matsumoto56 analyzed 29 random-
of people .70 years do not meet this RDA.42 Taking a low ized controlled trials investigating the effects of testosterone

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replacement in older men. Some studies found an increase in mass, strength, and physical performance. The strongest
lean body mass and hand grip strength but no effect on knee evidence for the use of GH supplementation appears to be
extension and flexion strength.56 Other studies have shown in states of reduced GH secretion. In younger GH deficient
up to 25% increase in leg strength in as little as 4 weeks of adults, GH supplementation for 3 years increased thigh
therapy.57 Some ­studies have found no increase in muscle muscle mass, strength, and improved exercise capacity.71
strength or f­unction but an improvement in lean body mass.58 However, in healthy non-GH deficient older people results
­Testosterone ­supplementation has been shown to increase the are more controversial. Some studies have shown an increase
size of the prostate gland in men.59 This could be detrimental in muscle mass but no improvement in muscle strength,
to men older than 60 years in which the prevalence of early whereas others have shown an increase in both muscle mass
stage prostate cancer is already high.60 The Baltimore Longi- and strength after administration of GH supplementation.72–74
tudinal Study on Aging involving 781 men showed a positive The failure of exogenous GH to mimic the pulsatile pattern of
correlation between prostate cancer and the blood concentra- normal GH secretion has been blamed for the negative results.
tion of free testosterone levels. The likelihood of acquiring Alternative potential hormonal interventions include the use
a high risk prostate cancer in men .65 years doubled for of GH releasing hormone which was found to have only a
every 0.1 unit increase in free testosterone.61 This along with small improvement in muscle strength in older men.75
other ­potential side effects of testosterone therapy like fluid It is well known that muscle strength increases as a result
­retention, gynecomastia, polycythemia, and sleep apnea limit of resistance exercise training in older adults.30,33 It was hypoth-
its usefulness as a treatment for sarcopenia.59,62,63 esized that the combination of GH replacement and exercise
training may have a synergistic effect on muscle function
Estrogens in older people. However, results proved disappointing and
The menopause is linked to reduced concentrations of cir- the addition of GH supplementation does not augment the
culating estradiol in middle aged and older women. There improvements in skeletal muscle brought about by exercise
appears to be impaired muscle performance during the alone.76,77 Low GH levels alone, therefore, may not be respon-
postmenopausal period when ovarian hormone production sible for the leveling off of muscle strength seen in older exer-
has decreased.64 It is easy to hypothesize that estrogens may cising people and that other pathways may be involved.
play a role in sarcopenia in older women. As it currently stands the evidence for the use of GH
The effect of hormone replacement therapy (HRT) in women supplementation to counter the effects of sarcopenia in older
is controversial. HRT may attenuate the loss of muscle mass people is weak. Moreover, the majority of trials involving
which occurs in the perimenopausal period.65 Estrogen replace- GH replacement therapy in older people have reported a high
ment therapy has only modest benefits on muscle composition incidence of side effects, including increased fluid retention,
and this may not translate to improved physical functioning.66 gynecomastia, orthostatic hypotension, and carpel tunnel
HRT combined with resistance training may have a role in syndrome.72,78
improving lower extremity function; however, more evidence
is needed.67 HRT has been implicated as a risk factor for breast Vitamin D
cancer and is, therefore, not recommended for sarcopenia.68 Vitamin D levels decline with age and cutaneous vitamin
D levels are up to four times lower in older compared with
Growth hormones younger individuals.79 It is known that vitamin D plays an
GH is required for maintenance of muscle and bone. GH important role in bone and muscle metabolism. Several
exerts most of its anabolic actions through IGF-1 which is mechanisms have been suggested for the role of vitamin D in
synthesized in the liver for systemic release. IGF-1 helps muscle function. Vitamin D binding to the vitamin D receptor
improve muscle function by increasing production of muscle found in skeletal muscle promotes muscle protein synthesis
satellite cells as well as stimulating production of muscle and enhances calcium uptake across the cell ­membrane.80
contractile proteins.69 Not only do GH and IGF-1 levels Low vitamin D levels result in atrophy predominantly of the
decline with age, the amplitude and frequency of pulsatile type 2 (fast twitch) muscle fibers in common with sarcope-
GH release is also significantly reduced.70 nia.81 Low levels of vitamin D have been found to be associ-
Despite a number of studies which have assessed the ated with an increase in sarcopenia.82 A myopathy has been
administration of GH supplementation, there is still an ongo- reported in severe vitamin D deficiency.83 In older people low
ing debate as to the use of GH supplementation on muscle vitamin D levels may produce functional problems including

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proximal muscle weakness, difficultly rising from a chair, dif- trials are required with a longer follow-up period in order
ficulties in ascending stairs, and axial balance problems.84 to assess the safety profile of vitamin D supplementation in
The evidence for a benefit in physical performance with older people before it is recommended as a treatment for
supplementation of vitamin D is controversial. Some studies sarcopenia in clinical practice.
have shown an improvement in muscle strength with inter-
mittent dosing and others have shown small gains in lower Angiotensin-converting enzyme inhibitors
extremity strength and less body sway with daily dosing.85 Angiotensin-converting enzyme (ACE) inhibitors have long
This improvement has been hypothesized as the mechanism been used as a treatment in primary and secondary prevention
behind a fall reduction of 23%–53% in older nursing or in cardiovascular disease as well as ­secondary stroke preven-
residential home residents given vitamin D in addition to a tion. It has now been suggested that ACE inhibitors may have a
reduction in fractures.86–88 beneficial effect on skeletal muscle. ACE inhibitors may exert
Conversely, other studies have found no benefits on their beneficial effects on skeletal muscles through a number of
physical function, falls risk or quality of life with vitamin D different mechanisms (Figure 2). ACE inhibitors may improve
supplementation in vitamin D deficient people.89–91 The differ- muscle function through improvements in endothelial function,
ence in findings between studies may in part be attributed to metabolic function anti-inflammatory effects, and angiogenesis
differences in the dose of vitamin D used with better outcomes thereby improving skeletal muscle blood flow. ACE inhibitors
seen when higher doses are used.92 It has also been suggested can increase mitochondrial numbers and IGF-I levels thereby
that there is a gender difference in outcomes with women helping to counter sarcopenia.102–107 People with the II geno-
standing to gain more from ­supplementation.92 ­Variations type of the ACE gene who have low serum ACE levels show
between study populations may also affect outcomes with an increased response to physical endurance.108,109 Therefore,
the biggest improvements in muscle function and physical lowering serum ACE levels with ACE inhibitors may have a
performance seen in institutionalized older people. beneficial effect on physical function. Observational studies
The prevalence of vitamin D insufficiency (25(OH)D have shown that the long-term use of ACE inhibitors was
levels ,40 nmol/L) in older people is high between 50% associated with a lower decline in muscle strength and walk-
and 75% especially in the northern latitudes and low levels ing speed in older hypertensive people and a greater lower
have been found even in summer months.93–95 A European limb lean muscle mass when compared with users of other
epidemiological study showed the prevalence of vitamin D antihypertensive agents.110,111 Several studies have shown that
deficiency in older adults aged 71–76 years was 36% in older ACE inhibitors improved exercise capacity in younger people
men and 47% in older women.96 It is recommended that with heart failure and this was also confirmed in older people
25(OH)D levels ,40 nmol/L requires supplementation and with heart failure,110,112,113 no improvement in grip strength.114
25(OH)D levels of .75 nmol/L is the level for optimum Although this could be largely attributed to improvements in
bone and muscle health.97 The recommended daily intake of cardiac function, skeletal muscle atrophy is also associated
vitamin D is between 400 IU and 600 IU per day which may with chronic heart failure so the evidence in muscle gains
be inadequate to raise serum vitamin D levels to a desirable should not be discounted.
level .70 nmol/L.98,99 Studies have shown that in order to Few interventional studies using ACE inhibitors for
achieve optimal levels of 75–100 nmol/L of 25(OH)D doses ­physical function have been undertaken. One study looking
between 700 and 1,000 IU would be needed.90 In the United at functionally impaired older people without heart failure
States, fortification of food such as milk and orange juice is has shown that ACE inhibitors increase 6-minute walk-
mandatory, whereas in the UK only margarine is ­fortified with ing distance to a degree comparable to that achieved after
vitamin D. The question of whether it should be ­mandatory 6 months of ­exercise training.115 Another found that ACE
for UK food products to be fortified with vitamin D remains inhibitors increased exercise time in older hypertensive
controversial. men.116 However, a study comparing the effects of nifedipine
Although it is plausible to associate low levels of vitamin D with ACE inhibitors in older people found no difference
with a reduction in muscle strength and ­physical function, between treatments in muscle strength, walking distance, or
the evidence for supplementation has been ­inconsistent. functional performance.117 It is possible that frailer subjects
Safety issues surrounding vitamin D supplementation in with slower walking speeds, who have a tendency to more
older people include increased risk of nephrolithiasis and cardiovascular problems, benefit more. This is reflected in
hypercalcemia.100,101 Further large randomized controlled the fact that adults with severe peripheral vascular disease

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Muscle fibers
Shift type I→II
↑ muscle fibre area
↑ aerobic activity

Angiogenesis
↑ endothelial cell
growth ACE Neurohormonal
↑ sympathetic activity
↑ skeletal muscle blood INHIBITORS
↑ neuromuscular
flow
transmission

Metabolic
↑ insulin sensitivity
↑ glucose uptake
↑ mitochondrial
Inflammation
activity ↓ IL6, ↓TNF-ά
↓ muscle loss
↓ muscle loss

Figure 2 Effects of ACE inhibitors on skeletal muscle.

Abbreviations: ACE, angiotensin-converting enzyme; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.

significantly increase their walking time following treatment over whether creatine supplementation increases the benefits
with ACE inhibitors.118 of resistance training alone in older people. Some studies
Further evidence is required before recommending ACE have found no added benefit of creatine supplementation to
inhibitors to counter the effects of sarcopenia. However, ACE resistance exercise training and other studies have found a
inhibitors are associated with cardiovascular benefits and small increase in lean tissue mass with no residual benefit
as older people frequently have underlying cardiovascular once resistance training was stopped.125–127
problems these agents are already commonly prescribed. Creatine is a natural ingredient of food and the main
source is from meat products with an average daily intake
Creatine of 1 g/day. However, creatine supplementation may increase
Creatine plays an important role in protein metabolism and the risk of interstitial nephritis highlighting the need for
cellular metabolism. It has been hypothesized that creatine particular caution about its use in older people.128 Creatine
increases the expression of myogenic transcription factors is not currently recommended for sarcopenia.
such as myogenin and myogenic regulatory factor-4, which
increases muscle mass and strength.119 Creatine supplemen- Myostatin
tation increases muscle phosphocreatine levels leading to a Myostatin is a natural inhibitor of growth factor. It was ­initially
decrease in muscle relaxation time.120,121 This may increase discovered when mutations of the myostatin gene was found
the ability to perform high-intensity exercise as well as to correlate with exaggerated muscle ­hypertrophy.129 The
enhance muscle protein synthesis, lean skeletal muscle mass, myostatin gene appears in skeletal muscle cells and functions
and strength during periods of high intensity training. as a negative regulator of muscle growth, ­antagonism of
To dates, several studies of creatine supplementation which increases satellite cell ­proliferation.130 In animal
have shown increased muscle strength and power in younger models, it appears that over expression of myostatin induces
men and women but few studies have looked at the effect extensive muscle loss.131 Polymorphisms of the myostatin
of creatine supplementation in older people. Some ­studies gene in humans correlated with measure of muscle mass,
have reported no effect of creatine supplementation on strength, and physical performance.132
muscle strength or function.122,123 However, others have Agents which target the myostatin pathway may be useful
reported increments in muscle mass and increased muscle in increasing muscle mass and, therefore, play a vital role in
power without adverse effects.122,124 There is controversy muscle wasting disorders as well as sarcopenia of old age.

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Dovepress Optimal management of sarcopenia

Phase II trials have been carried out in muscular dystrophy treatment options to counter the process of sarcopenia are
and initial results have shown that MYO-29, a recombinant being developed. Recent evidence has shown ACE inhibi-
antibody to myostatin, had good safety and tolerability pro- tors can improve muscle exercise capacity in functionally
file.133 Another potential therapeutic approach in development impaired older people; however, further randomized con-
is a soluble activin type 2B receptor that binds to the myo- trolled trials are required. Other future prospects including
statin and, therefore, reducing its availability. Initial results the so called “exercise pill” have suggested potential methods
in mice have shown an increase in muscle weight larger than to improve muscle performance in later life.
those achieved with myostatin inhibitors.134
Inhibition of myostatin with follistatin (myostatin antago- Disclosure
nist) may have potential therapeutic benefits in the treatment of The authors report no conflicts of interest in this work.
sarcopenia. Although myostatin deficiency increased muscle
mass in mice it impaired, the structure and function of the mus-
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