Skeletal muscle loss: cachexia, sarcopenia, and inactivity
William J Evans
Loss of skeletal muscle mass occurs during aging (sarcopenia), dis-
ease (cachexia), or inactivity (atrophy). This article contrasts and com-
pares the metabolic causes of loss of muscle resulting from these
conditions. An understanding of the underlying causes of muscle loss
is critical for the development of strategies and therapies to preserve
muscle mass and function. Loss of skeletal muscle protein results from
an imbalance between the rate of muscle protein synthesis and deg-
radation. Cachexia, sarcopenia, and atrophy due to inactivity are char-
acterized by a loss of muscle mass. Each of these conditions results in
a metabolic adaptation of increased protein degradation (cachexia),
decreased rate of muscle protein synthesis (inactivity), or an alteration
in both (sarcopenia). The clinical consequences of bedrest may mimic
those of cachexia, including rapid loss of muscle, insulin resistance,
and weakness. Prophylaxis against bedrest-induced atrophy includes
nutrition support with an emphasis on high-quality protein. Nutri-
tional supplementation alone may not prevent muscle loss secondary
to cachexia, but, in combination with the use of an anabolic agent, it
may slow or prevent muscle loss. Am J Clin Nutr 2010;91
Cachexia is a metabolic condition that is always associated
with an underlying illness and inﬂammation. It is characterized
by loss of skeletal muscle and body weight. Nutritional inter-
ventions have shown limited success in preserving fat but not
muscle mass. Sarcopenia is the age-associated loss of skeletal
muscle and function. Sarcopenia is a life-long process with
a complex and multifactorial etiology. The effects of inactivity,
and in particular bedrest, may mimic those of cachexia. However,
there are important metabolic distinctions with signiﬁcant nu-
Cachexia has long been recognized as a condition associated
with a number of chronic diseases and acute medical conditions.
Cachexia has been deﬁned by Evans et al (1) as “a complex
metabolic syndrome associated with underlying illness and
characterized by loss of muscle with or without loss of fat mass.
The prominent clinical feature of cachexia is weight loss in
adults” (p 795). Although cachexia is associated with both fat and
muscle loss, the beneﬁts of preserving skeletal muscle or body fat
stores is still unresolved. The most obvious manifestation of
cachexia is loss of body mass, and in many chronic conditions
this loss of body mass may be rapid. Weight loss is associated
with a signiﬁcant increase in mortality risk (2) in patients with
heart failure. Fat tissue wasting (lipolysis) is less well deﬁned
but appears to be regularly present in patients with weight loss
associated with malignant cancers (3), chronic heart failure (4), or
chronic kidney disease (5). Chronic obstructive pulmonary disease
(COPD) is associated with inﬂammation and muscle wasting (6).
Clinical studies have shown that the preservation of body fatness
and skeletal muscle in cachectic patients can decrease mortality
risk (2, 7, 8). However,important questions remain in the treatment
of cachexia. If the metabolic consequence of cachexia is loss of
skeletal muscle, will strategies to conserve muscle in cachectic
conditions improve mortality and morbidity? Weight loss and
extreme loss of body fat are the most obvious clinical manifestation
of cachexia. Do strategies designed to maintain body weight,
irrespective of composition of the weight, have a positive inﬂuence
on outcomes? In addition, as cachexia is associated with an un-
derlying disease, patients are often hospitalized or become ex-
tremely inactive as a result of the manifestations of the disease. Is it,
therefore, possible to separate the effects of immobilization and
inactivity from the metabolic effects of cachexia?
SKELETAL MUSCLE AND CACHEXIA
As noted, muscle wasting is important in the pathophysiology
of cachexia and a major cause of fatigue (9) in patients. Ac-
celerated or exaggerated loss of skeletal muscle mass dis-
tinguishes cachexia from weight loss that is due solely to reduced
energy intake. Several groups of investigators have suggested that
actomyosin, actin, and myosin are selectively targeted for deg-
radation in clinical conditions associated with cachexia (10–12).
Acharyya et al (10) wrote that “cachectic factors are remarkably
selective in targeting myosin heavy chain.” In mice with colon-26
tumors, they found that 2 markers of inﬂammation that are
typically elevated with cachexia, tumor necrosis factor-aand
interferon-c, reduce the expression of myosin. They also re-
ported that loss of myosin protein was associated with the
ubiquitin-dependent proteosome pathway. These data suggest
that myosin is a speciﬁc target and that both protein-degradative
and synthetic pathways are inﬂuenced. Selective targeting of
skeletal muscle is at least in part due to the systemic in-
ﬂammation that frequently accompanies clinical conditions as-
From the Division of Geriatrics, Department of Medicine, Duke Univer-
sity Medical Center, Durham, NC.
Presented at the symposium “Cachexia and Wasting: Recent Break-
throughs in Understanding and Opportunities,” held at Experimental Biology
2009, New Orleans, LA, 18 April 2009.
Address correspondence to WJ Evans, Muscle Metabolism Unit, Glaxo-
SmithKline, MS R&D N2-2204A, 5 Moore Drive, Research Triangle Park,
NC 27709. E-mail: email@example.com.
First published online February 17, 2010; doi: 10.3945/ajcn.2010.28608A.
Am J Clin Nutr 2010;91(suppl):1123S–7S. Printed in USA. Ó2010 American Society for Nutrition 1123S
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sociated with cachexia. Indeed, Lecker et al (13) concluded that
a common transcriptional program is associated with skeletal
muscle atrophy in animals that are fasting, or have uremia,
cancer, or streptozotocin-induced diabetes. Among the strongly
induced genes were many involved in protein degradation, in-
cluding polyubiquitins, Ub fusion proteins, the Ub ligases
atrogin-1/MAFbx (muscle atrophy f box) and MuRF-1 (muscle-
speciﬁc RING ﬁnger-1), multiple but not all subunits of the 20S
proteasome and its 19S regulator, and cathepsin L. The common
feature of cachexia, loss of muscle mass, suggests that therapies
targeting muscle or inﬂammatory pathways that have a direct
effect on skeletal muscle may be effective in reducing the
devastating effects of cachexia. It also appears that the rate of
muscle protein degradation is up-regulated. Indeed, nuclear
transcription factor jB (NF-jB) activation may be an important
regulator of skeletal muscle proteasome expression and protein
degradation. Inhibitors of NF-jB completely attenuated protein
degradation in murine myotubes and the NF-jB inhibitor re-
sveratrol signiﬁcantly attenuated weight loss and muscle protein
degradation in mice bearing the MAC16 tumor (14).
Cachexia is also associated with a reduction in circulating
anabolic hormones. Testosterone concentrations are greatly re-
duced in patients with cachexia, resulting in a down-regulation in
the rate of muscle protein synthesis. Although circulating growth
hormone and insulin-like growth factor-I (IGF-I) appear to be
unchanged (compared with normal concentrations) in patients
with heart failure, Hambrecht et al (15) described a resistance of
skeletal muscle to the inﬂuence of growth hormone, including
a 52% reduction in expression of IGF-I and IGF-I receptor.
Loss of body weight, fat, and skeletal muscle has been as-
sociated with increased mortality in patients with cachexia.
COPD is associated with cachexia. In these patients, loss of
appetite (16), decreased body weight, and low testosterone
concentration (17), muscle mass, and functional status have been
reported. Along with these changes, a large increase in NF-jB
activation in skeletal muscle has been documented (18) and an
increased rate of whole-body muscle protein breakdown (19) has
been observed in underweight (cachectic) patients with COPD.
Schols et al (8) examined .400 patients with COPD, and found
that skeletal muscle mass was an independent risk for increased
mortality and that body fatness presented no associated risk.
Although delivery of nutrition in patients with cachexia may
provide energy and amino acids for protein synthesis, in certain
cachectic conditions, providing energy and protein maintains
weight but not muscle mass. In burn patients, providing con-
tinuous enteral feeding to .1.2 ·resting metabolic rate in-
creased fat mass with no effect on muscle mass (20). In patients
with severe sepsis, delivery of total parenteral nutrition pre-
served fat mass, with no effects on skeletal muscle mass (21). In
these patients, weight loss occurred when delivery of energy was
less than total energy expenditure that increased as a result of
a substantial increase in basal metabolic rate. Thus, fat mass can
be preserved or increased in cachectic patients with appropriate
delivery of energy. However, delivery of protein in these patients
does not appear to preserve muscle mass.
Reduction in lean body mass, and an accompanying increase in
fat mass, are among the most striking and consistent changes
associated with the advance of age. Skeletal muscle (22) and bone
mass are the principal components of lean body mass to decline
with age. Sarcopenia was originally described by Evans and
Campbell (23) and was further deﬁned by Evans (24) as age-
related loss of muscle mass. Subsequently, a number of authors
have deﬁned sarcopenia more speciﬁcally as a subgroup of older
persons with muscle-mass depletion, usually deﬁned as being
2 SD below the mean muscle mass of younger persons (typically
expressed as age 35 y) (25). This loss of muscle results in
a decrease in strength, metabolic rate, and aerobic capacity and
thus, in functional capacity. Newman et al (26) has shown that
muscle function (strength), rather than mass, is associated with
Loss of skeletal muscle with advancing age begins relatively
early, and continues until the end of life (22). From 20 to 80 y of
age, there is an ’30% reduction in muscle mass and a decline in
cross-sectional area of ’20% (27). This is due to a decline in
both muscle ﬁber size and number (28). There is no consensus
on whether there is a selective loss of speciﬁc muscle ﬁber types.
Early cross-sectional studies demonstrated a shift in muscle ﬁber
composition with a higher type I/type II ﬁber ratio with ad-
vancing age (29). Larsson (30) suggested a preferential loss of
type II ﬁbers with advancing age, potentially starting in early
adulthood. Type II ﬁbers show selective atrophy (with a preser-
vation of type I ﬁber area) with age (31).
The etiology of sarcopenia is multifactorial and complex.
Factors that have been implicated for sarcopenia include de-
creased physical activity level (32), declining androgen con-
centrations (33), speciﬁc nutritional deﬁciencies (dietary protein
and vitamin D) (34), chronic inﬂammation (35, 36), insulin re-
sistance (37), and a number of other factors. Importantly, ca-
chexia may also contribute to sarcopenia. The effects of
inactivity/sarcopenia compared with those of cachexia are shown
in Table 1.
DECREASED PHYSICAL ACTIVITY
Decreased physical activity that occurs with aging may con-
tribute to age-related sarcopenia. The relation between skeletal
muscle mass and level of physical activity is complex. Reduction
in physical activity alters body composition in a number of ways.
Muscle mass is decreased while fat mass is increased (38).
Hughes et al (39) examined body composition and physical
activity in 54 men and 75 women over a 10-y period (age: 60.7 6
7.8 y at baseline) and showed that higher levels of physical
Comparison of the metabolic consequences of inactivity/sarcopenia to
Muscle protein synthesis Increased Increased
Muscle protein degradation No change Increased
Muscle mass, strength, and function Decreased Decreased
Fat mass Increased Decreased
Basal metabolic rate and total
Inﬂammation No change Increased
Insulin resistance Increased Increased
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activity attenuated the progression of sarcopenia. However,
changes in fat-free mass may be attenuated by increased fat
mass (40). That is, increasing body fatness, even in elderly
people, is associated with increased muscle mass. Loss of bone
mass (osteopenia) and sarcopenia are closely linked and are
strongly affected by level of physical activity in pre- and post-
menopausal women (41) and in older men (42). The rate of
muscle loss is accelerated even more when an older person
undergoes a period of enforced bedrest due to illness.
From the early studies of Cuthbertson (43) and Deitrick et al
(44) to the more recent studies (45, 46), one of the most con-
sistent and reproducible effects of prolonged bedrest is an in-
crease in nitrogen excretion. Although early studies failed to
distinguish between an increase in the rate of degradation of
protein and a decrease in the rate of protein synthesis, it was well
recognized that the source of the increased nitrogen excretion is
skeletal muscle. The early studies of bedrest immobilization by
Cuthbertson (43) and Deitrick et al (44) showed an increased
muscle wasting signiﬁed by an increased nitrogen excretion.
Studies using orally or intravenously administered isotopically
labeled amino acids in space-ﬂown and bed-rested individuals
showed alterations in protein synthesis and degradation, with
a net decrease in protein balance (47–49). Taken together, these
data suggest that changes in protein metabolism during periods of
bedrest or immobilization may in part be a result of decreased
Whole-body protein breakdown is not affected by bedrest (47,
50). Shangraw et al (47) examined the effects of 7 d of strict
bedrest on indexes of protein metabolism in 6 men (age: 21–
28 y). They found that bedrest increased nitrogen excretion and
resulted in an average cumulative loss of 6.3 g nitrogen, and
magnetic resonance imaging of the back and lower extremities
revealed a 1–4% decrease in muscle volume. They observed no
increase in whole-body protein breakdown. These data along
with no increase in 3-methylhistidine excretion led the authors to
conclude that the increased nitrogen and muscle loss resulted
from an inhibition of protein synthesis. Stuart et al (49) showed
that increasing dietary protein intake attenuates the rate of ni-
trogen loss in bed-rested subjects. In young subjects, 14 d of
bedrest resulted in loss of whole-body nitrogen, with a greater
loss during the second week of bedrest. Leg and whole-body lean
mass also decreased after bedrest. Fractional protein synthesis
decreased by 46%. The authors concluded (45, 46) that the loss of
body protein with inactivity was predominantly due to a decrease
in muscle protein synthesis. Small amounts of activity may be
sufﬁcient to attenuate loss of muscle, such as in loading muscle
(increasing force production), when subjects are supine (50).
These authors also showed that bedrest had no effect on the rate of
muscle protein degradation, and muscle loading increased the
rate of protein synthesis. Bedrest signiﬁcantly lowered daily total
energy expenditure (TEE) (51). Gretebeck et al (51) showed that
10 d of bedrest caused a 21% reduction in TEE with a TEE/basal
metabolic rate of 1.2. Cachexia associated with sepsis, on the
other hand, resulted in a substantial increase in resting energy
expenditure and TEE (20).
Elderly people are the most likely to be placed in bed because
of illness, trauma, loss of balance, or increasingly because of
a greatly diminished functional capacity. Very often, the most
frail and medically compromised individual is placed in bed for
extremely long periods of time. National statistics show that
increasing age is associated with a longer average length of stay
in a hospital and patients older than 65 y account for .35% of all
hospital discharges (52). A recent study showed that older
people respond to an extended period of bedrest with a far
greater loss of skeletal muscle mass than do young people (32).
In this study, healthy older people (mean age: 67 y) responded to
10 d of bedrest with a loss of ’1 kg of muscle from the lower
extremities. In this study, the fractional synthetic rate (FSR) of
skeletal muscle protein, measured over a 24 h period was re-
duced by 30% after the bed-rest period. This is contrasted to
,500 g of muscle lost after 28 d of bedrest in young people
(53). This decreased muscle mass due to bedrest in older sub-
jects was associated with large reductions in strength, aerobic
capacity, and amount of physical activity. In addition, percent-
age of time that subjects spent inactive increased (7.6 61.8%,
P= 0.004) (54). This increased loss of skeletal muscle, strength,
and functional capacity in an elderly man or woman as a result
of bedrest is very likely to make a frail but ambulatory and
independent individual become nonambulatory, with an ac-
companying loss of functional independence. This group of in-
vestigators also showed that a supplement of essential amino
acids (15 g provided 3 times daily) greatly attenuated the loss of
muscle mass, decrease in FSR, and the large increase in nitrogen
The effects of prolonged inactivity due to illness or hospi-
talization will result in accelerated loss of skeletal muscle and
functional capacity. In a number of ways, these changes mimic
those of cachexia. A major feature of cachexia is a rapid loss of
skeletal muscle. In addition to inﬂammation and an increased
muscle protein fractional breakdown rate, cachexia is associated
with insulin resistance, fatigue, muscle weakness, anemia, and an
increase in metabolic rate and total energy expenditure (1). If
bedrest results in a large down-regulation in muscle FSR, ca-
chexia increases the fractional breakdown rate with a compen-
satory increase in muscle FSR. This is due to the stimulatory
effect of increasing the intramyocellular free amino acid pool on
The precise wording of the consensus deﬁnitions of cachexia
and sarcopenia are as follows:
Cachexia: “Cachexia is a complex metabolic syndrome associ-
ated with underlying illness and characterized by loss of
muscle with or without loss of fat mass. The prominent clin-
ical feature of cachexia is weight loss in adults (corrected for
ﬂuid retention) or growth failure in children (excluding en-
docrine disorders). Anorexia, inﬂammation, insulin resistance
and increased muscle protein breakdown are frequently asso-
ciated with cachexia. Cachexia is distinct from starvation,
age-related loss of muscle mass, primary depression, malab-
sorption, and hyperthyroidism and is associated with in-
creased morbidity” (56).
Sarcopenia: “Sarcopenia is the age-associated loss of skeletal
muscle mass and function. The causes of sarcopenia are mul-
tifactorial and can include disuse, changing endocrine func-
tion, chronic diseases, inﬂammation, insulin resistance, and
nutritional deﬁciencies. Whereas cachexia may be a compo-
nent of sarcopenia, the 2 conditions are not the same. The
SKELETAL MUSCLE LOSS 1125S
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diagnosis of sarcopenia should be considered in all older pa-
tients who present with observed declines in physical func-
tion, strength, or overall health. Sarcopenia should speciﬁcally
be considered in patients who are bedridden, cannot indepen-
dently rise from a chair, or who have a measured gait speed
,1.0 m s
. Patients who meet this initial criteria should
further undergo body composition assessment using dual-
energy X-ray absorptiometry with sarcopenia being deﬁned
as an appendicular lean/fat mass 2 SD less than that of young
adult. A diagnosis of sarcopenia is consistent with a gait speed
of ,1 m/s and an appendicular lean/fat ratio ,2 SD of the
average of a young adult” (unpublished data, Sarcopenia Con-
sensus Conference, Rome, Italy, November 2009).
The author is employed at the Muscle Metabolism unit at GlaxoSmith-
Kline. There were no other potential conﬂicts of interest.
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