CHAPTER 49

PERIPHERAL MUSCLE
DYSFUNCTION IN CHRONIC
OBSTRUCTIVE PULMONARY
DISEASE
Richard Debigar, Franois Maltais

ough, dyspnea, and exercise intolerance are among the

early clinical manifestations of chronic obstructive pulmonary disease (COPD).1 As the disease progresses, several
extrathoracic organs are affected, such that COPD is now
recognized as a multisystem disease. Altered kidney and
endothelial function,2 endocrine abnormalities,3 osteoporosis,4 and peripheral muscle dysfunction5 are now commonly
reported in COPD. Among these extrathoracic manifestations of COPD, the involvement of the peripheral muscles is
the subject of intense research because it may influence
quality of life, functional status, and survival independently
of the alteration in lung function. Thus, the improvement in
peripheral muscle function represents a potential and valid
therapeutic target for many patients with COPD.
Our understanding of the mechanisms underlying the
alteration in peripheral muscle function in COPD is in its
early stages. Although promising pathophysiologic concepts
are emerging from experimental models, such as cultured
muscle cells and cachectic animals, the precise mechanisms
of the alterations in peripheral muscle function seen in
chronic diseases such as COPD have yet to be elucidated.
In this chapter, we discuss the evidence for and clinical
consequences of peripheral muscle dysfunction in COPD
and review potential mechanisms of muscle wasting. Finally,
actual and future therapies that stop muscle proteolysis or
increase muscle mass are discussed.

EVIDENCE OF PERIPHERAL MUSCLE

DYSFUNCTION
Body weight loss and muscle wasting in COPD-affected subjects have long been recognized by clinicians,6 and many
reports have confirmed the high prevalence of this phenomenon.7 Furthermore, the peripheral muscles in patients with
COPD are affected not only quantitatively (wasting) but also

qualitatively, as illustrated by the marked alterations in

fiber-type distribution and decreased metabolic capacity.
The quadriceps is the most commonly studied peripheral
muscle, not only because it is readily accessible but also
because it is a primary effector muscle of ambulation. Since
most studies have included patients with moderate-tosevere disease, the muscle changes reported herein pertain
to this patient population.

MUSCLE MASS
Peripheral muscle wasting is an important consequence of
COPD (Figure 49-1), with an overall estimated prevalence of
30%.7 The prevalence of this problem increases with the
degree of airflow obstruction. A key concept is that muscle
mass may be low despite the preservation of total body
weight.7 The implication of this is that the prevalence of muscle wasting is likely to be underestimated if one relies only on
measurements of body weight. Another implication is that in
patients with COPD, there is a preferential loss of muscle
tissue in comparison with other body compartments.8,9

MUSCLE FIBER TYPE, SIZE,

AND

CAPILLARIZATION

Human skeletal muscle fibers can be grouped into separate

categories on the basis of their physiologic and metabolic
characteristics. Type I fibers are characterized by low contractile velocity and high oxidative capacity (which account
for their relative resistance to fatigue), whereas type IIb
(or IIx) fibers have a high contractile velocity and a lower
oxidative capacity (and therefore are more prone to
fatigue).5 Type IIa fibers are intermediate between types I
and IIb.5 The fiber-type profile, an important determinant of
muscle metabolic capacity, has been assessed in patients
with COPD by using both classic histochemical fiber typing
and analysis of myosin heavy-chain isoform expression. In
patients with mild-to-moderate airflow obstruction, the

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Exercise Physiology

COPD. These two enzymes, which are involved in the citric

acid cycle and -oxidation of fatty acids, respectively, are
good markers of muscle oxidative capacity. In contrast to the
above findings, Sauleda and colleagues have reported higher
activity of cytochrome c oxidase, a key enzyme of the electron transport chain (the last step of the oxidative pathway),
in COPD patients than in healthy controls.14 This finding is
unexpected, given that the activities of all mitochondrial
enzymes usually vary in a coordinated fashion. The significance of this apparently uncoordinated expression of mitochondrial enzymes in patients with COPD needs to be
further investigated.

Fiber-type proportion (%)

FIGURE 49-1 Computed tomography scans of one healthy subject

(left panel) and one patient with chronic obstructive pulmonary
disease (COPD) (right panel) of the same age group. The thigh
muscle cross-sectional area was considerably reduced in the COPD
patients in comparison with normal subject. Reproduced with
permission from Bernard S et al.8

100
90
80
70
60
50
40
30
20
10
0

Normals
COPD

Type I

Type IIa

Type IIab

Type IIb

FIGURE 49-2 Fiber-type proportions of the vastus lateralis muscle

found in normal subjects and in patients with chronic obstructive
pulmonary disease (COPD). As can be seen, a significant reduction
in the proportion of type I fibers was found, with a corresponding
increase in the proportion of type IIb fibers, in patients with
COPD in comparison with normal subjects. Values are mean SD.
*p .0005, **p .015. Reproduced with permission from
Whittom F et al.11

proportion of type I fibers is preserved.10 In patients with

more advanced airflow obstruction, there is a reduction in
the proportion of type I fibers (17 to 29% vs 45 to 50% in
COPD and normal subjects, respectively), with a reciprocal
increase in type IIb fibers11 (Figure 49-2). In COPD, type I
and IIa fibers are atrophic, and the number of capillaries in
contact with them is reduced in comparison with agematched healthy subjects.11 The reduction in type I and IIa
fiber cross-sectional area is proportional to the reduction in
midthigh cross-sectional area, suggesting that the loss in vastus lateralis muscle mass is mostly due to specific type IIIa
fiber atrophy.

MUSCLE METABOLIC CAPACITY

In line with the fiber-type profile described above, low activity of two mitochondrial enzymes, citrate synthase12,13 and
3-hydroxyacyl-CoA dehydrogenase,13 has been reported in
needle biopsy specimens of the vastus lateralis muscle in

PERIPHERAL MUSCLE METABOLISM AT

AND DURING EXERCISE

REST

In keeping with the morphologic and enzymic muscle

changes, muscle energy metabolism is modified at rest and
during exercise in COPD. At rest, low intracellular pH,
reduced phosphocreatine (PCr) and ATP concentrations,
and increased lactate and inosine monophosphate concentrations have been found in the vastus lateralis muscle.15
When nuclear magnetic resonance spectroscopy (31P-NMR)
was used to study the oxidative metabolism of skeletal
muscle during exercise (reviewed by Levy and colleagues16),
greater declines in muscle intracellular pH and PCr/inorganic
phosphate ratio were observed during exercise in patients
with COPD than in normal subjects. These findings are
indicative of impaired oxidative phosphorylation and ATP
resynthesis, with a high reliance on anaerobic glycolysis
within the contracting muscles. Although these exerciseinduced peripheral muscle metabolic abnormalities are
worsened by hypoxemia and can be partially reversed with
oxygen supplementation, they have also been reported in
patients with little or no reduction in peripheral oxygen
delivery,17 suggesting that altered muscle metabolism during
exercise is related, at least in part, to poor muscle oxidative
capacity or abnormal metabolic regulation.

UPPER EXTREMITY AND RESPIRATORY

VERSUS LOWER LIMB MUSCLES

MUSCLES

Interestingly, all peripheral muscles are not affected to

the same extent in patients with COPD. For instance, the
strength of the upper extremity muscles is relatively preserved in comparison with that of the lower extremities,8,18
and the activity of citrate synthase in the deltoid muscle
was found to be preserved in patients with severe COPD
in comparison with subjects with normal respiratory function.19 The adaptation of the diaphragm in COPD is also
different to that of the vastus lateralis muscle.20,21 Whereas
the vastus lateralis muscle shows a low capacity for aerobic
metabolism and increased susceptibility to fatigue,13 the
diaphragm is characterized by an increased proportion of
fatigue-resistant fibers.20,21 The observation of differential
adaptation of the respiratory, upper limb, and lower limb
muscles is intriguing and may lead to insights into the
mechanisms responsible for peripheral muscle dysfunction
in COPD (see below). For instance, differential adaptive
responses of the different muscle groups do not support the
presence of a generalized myopathic disorder but would be

Peripheral Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

consistent with involvement of local muscular events in the

deterioration of lower limb muscle function.

PERIPHERAL MUSCLE DYSFUNCTION

AND CLINICAL STATUS
Functional peripheral muscle tissue is necessary for activities of daily living and vital functions such as breathing and
eating. Moreover, muscle tissue can serve as an important
reservoir from which amino acids can be drawn to support
intense protein synthesis, such as during the systemic
inflammatory response to infections or injuries.22 The interactions between actin and myosin, which are responsible for
force production and movement, require a continuous supply of energy, which is ensured by ATP production by either
glycolytic or oxidative metabolism.5 The relative proportions of the different myosin isoforms determine the speed
of contraction, whereas the magnitude of force production is
proportional to the muscle cross-sectional area. It is thus
evident that alterations in muscle mass, morphologic characteristics, and enzymic characteristics will have negative
influences at numerous levels.

MUSCLE WEAKNESS

AND

ENDURANCE

In patients with moderate-to-severe airflow obstruction, the

quadriceps muscle strength is reduced by approximately
30%.8,18 The strength of the quadriceps muscle is an important determinant of exercise capacity in COPD.18 This may
be related to the influence of muscle strength on the perception of leg effort during exercise, the main limiting symptom
in 40 to 45% of patients with COPD.23 The question of
whether muscle weakness is merely the consequence of
muscle atrophy or contractile dysfunction and/or abnormal
neural recruitment may contribute to loss of strength has
been recently addressed. In patients with COPD, the quadriceps muscle strength/midthigh cross-sectional area ratio is
similar to that of normal subjects.8 To further address this
question, in vitro contractile properties of the vastus lateralis
muscle were studied in 16 patients with COPD and 9 control subjects.24 Muscle bundles from the vastus lateralis
muscle obtained by open biopsy were vertically suspended
in an organ bath, and their contractile properties were measured. This experimental setup is interesting because under
such conditions the maximal force production is totally
independent of motivational factors. The maximal isometric
peak forces, both in absolute values and normalized for the
muscle bundle cross-sectional area, were similar for COPD
and control subjects. On the basis of the in vivo and in vitro
data, it is concluded that the contractile properties of the
vastus lateralis muscle are preserved in patients with COPD.
Therefore, the reduction in quadriceps muscle strength in
patients with COPD can be explained not on the basis of
an alteration of the contractile apparatus but rather on the
basis of a loss in muscle mass. However, the loss in strength
may be out of proportion to the loss of muscle mass
in patients exposed to systemic corticosteroids.8,25 This is in
accordance with previous animal studies showing that
corticosteroids may alter muscle function without causing
muscle atrophy.26

569

In line with the histochemical and enzymic changes, the

resistance to fatigue of the vastus lateralis muscle, measured
during isometric contractions, is reduced in patients with
COPD.27

EXERCISE INTOLERANCE
Exercise intolerance is a major consequence of COPD, and
this fact cannot be explained solely on the basis of limitations in ventilation and gas exchange. For instance, the
degree of impairment in lung function is a poor predictor of
exercise capacity.28 Perhaps the most striking clinical observation pointing to a peripheral component of exercise limitation in COPD is that exercise capacity remains abnormally
low in most lung transplant recipients despite normalization
of lung function.29
In patients with COPD, exercise termination usually
occurs before a true plateau in oxygen consumption (VO2)
is reached. In many patients, psychological factors such as
anxiety, fear of dyspnea, and poor motivation may contribute
to exercise intolerance. As a result, the physiologic contribution of individual factors to reduced peak VO2 is difficult to
assess. The contribution of peripheral muscle abnormalities
to exercise limitation in COPD has been challenged by
Richardson and colleagues.30 These authors showed that the
aerobic capacity of the lower limb muscle was not reached
during cycling exercise (when a large muscle mass was
involved) because of the early occurrence of central limitation to exercise. The implication of this is that the aerobic
capacity of the exercising muscles of the lower limbs, even if
reduced, is not overwhelmed during whole body exercise in
patients with COPD. It must be remembered, however, that
patients with COPD stop exercising because of exertional
discomfort and not necessarily because of physiologic constraints. Leg fatigue is commonly perceived at peak exercise
in patients with COPD23; this could be related to the fact
that peripheral muscle alterations increasing susceptibility
to contractile fatigue, such as poor oxidative capacity, atrophy, and weakness, are common in this disease. In line with
these observations, Mador and colleagues31 confirmed that
contractile fatigue of the quadriceps muscle might occur
during exercise in patients with COPD. We recently evaluated the impact of leg fatigue on the exercise response to
acute bronchodilatation in patients with COPD in order to
test the hypothesis that the improvement in airflow obstruction should not translate into greater exercise capacity in
patients with higher susceptibility to leg fatigue.32 Patients
with COPD performed two constant-work-rate cycling exercises up to exhaustion. These tests were preceded by nebulization of placebo or 500 g of ipratropium bromide.
Muscle fatigue was defined as a postexercise reduction in
quadriceps muscle twitch force 15% of the resting value.
Nine patients developed contractile fatigue after placebo
exercise. In these patients, ipratropium bromide did not
increase endurance time, despite an 11% improvement in
forced expiratory volume in 1 second. In the nine patients
who did not show fatigue after placebo exercise, endurance
time was increased by ipratropium bromide. There was a
significant correlation between the improvement in
endurance time with ipratropium bromide and quadriceps

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Exercise Physiology

muscle twitch force at 10 minutes after placebo exercise. In

summary, improved exercise response after bronchodilatation may be prevented by concomitant leg fatigue, providing
direct evidence of the role of peripheral muscle dysfunction
in exercise intolerance in COPD.
Lower capacity for muscle aerobic metabolism may influence exercise tolerance in several ways. Increased lactic
acidosis for a given exercise work rate, which is a common
finding in COPD,13,33,34 increases ventilatory needs by
increasing nonaerobic carbon dioxide production.33 This
imposes an additional burden on the respiratory muscles,
which are already facing increased impedance to breathing.
In addition, the resulting acidemia may act as a breathing
stimulus through the carotid bodies. Premature muscle acidosis, a contributory factor to muscle fatigue and early exercise termination in healthy subjects, may be an important
mechanism contributing to exercise intolerance in COPD.17
This may be exacerbated by a tendency to retain carbon
dioxide (respiratory acidosis) during exercise.33
Our interpretation of the current literature is that
although muscle oxidative potential may not be fully used
during a maximal exercise test, the muscle atrophy and
weakness and the alterations in muscle metabolism during
exercise that have been repeatedly reported in COPD are
likely to influence the capacity to perform exercise by
increasing the perception of leg effort and the ventilatory
requirements and by contributing to the development of
contractile fatigue of the peripheral muscles.

OTHER CONSEQUENCES

OF

MUSCLE DYSFUNCTION

Other likely consequences of muscle wasting and poor

peripheral muscle function in COPD include reduction in
quality of life,35 greater utilization of health care resources,36
and poor survival.37

ETIOLOGY OF PERIPHERAL MUSCLE

DYSFUNCTION IN COPD
Several factors have been suggested to explain the occurrence of muscle dysfunction in COPD, and their relative
importance is likely to vary among patients. Peripheral muscle dysfunction is probably multifactorial in origin and is
unlikely to be explained by one mechanism in all patients.
Chronic inactivity,38 nutritional imbalance,39 systemic corticosteroid use,25 hypoxemia,40 systemic inflammation with
increased circulating levels of proinflammatory cytokines,41
electrolyte disturbances,42 and low anabolic hormone
levels43,44 have all been suggested as potential contributors
to the development of poor peripheral muscle function in
COPD. However, a causal link between these abnormal
states and the deterioration in muscle function has not been
established.
It is often supposed that muscle wasting in COPD is due
to an imbalance between caloric intake and energy expenditure, leading to a reduction in protein synthesis.39,45
However, attempts to increase nutritional intake have
resulted in only modest and inconsistent improvements in
body weight and muscle mass and strength (reviewed by
Ferreira and colleagues46). As in many chronic disorders,47

increased muscle proteolysis is likely to be present in

COPD and could explain the lack of efficacy of nutritional
interventions in ameliorating muscle dysfunction in
COPD.
A similar conclusion was reached with regard to several
other illnesses,22,48,49 leading to the development of the concept of cachexia. Cachexia (Greek: bad condition), in contrast to starvation, is characterized by preferential loss in the
muscle tissue compartment associated with systemic inflammation and lack of response to nutritional supplementation.22 The preferential loss of muscle tissue,8,9 the lack of
response to nutritional supplementation, and the presence
of low-grade systemic inflammation41 with increased blood
levels of proinflammatory cytokines50 strongly suggest that
the loss in body weight and muscle mass in patients with
COPD can be considered to constitute a state of cachexia.

REGULATION OF MUSCLE
AND DEGRADATION

PROTEIN SYNTHESIS

The muscle tissue is a primary reservoir of amino acids in

the body. In response to disease or fasting, amino acids
released from muscle tissue are mobilized to sustain liver
protein synthesis (acute-phase protein synthesis) or
immune cell replication, as well as for energy production
(gluconeogenesis).22 The amount of muscle tissue (ie, its
protein content) in a given individual is the result of a tight
balance between protein synthesis and breakdown.
Increased protein degradation is a hallmark of many diseases, such as cancer,22 sepsis,51 and chronic renal failure.49
For COPD, there have been only two studies in which protein metabolism was assessed, and their conclusions conflict.45,52 In comparison with healthy subjects, one study
found decreased protein synthesis in COPD patients,45
whereas the other52 found simultaneous increases in protein
synthesis and degradation, reflecting increased whole body
protein turnover. Lack of agreement between these studies
may be explained by the use of different techniques to measure protein metabolism, in addition to the disparity in the
subjects studied. Further studies of protein metabolism will
be needed to clarify this issue.

MUSCLE PROTEOLYSIS
There are different pathways for degrading proteins.
Lysosomes contain proteases that have optimal activity at an
acidic pH (eg, cathepsins) and degrade membrane or endocytosed proteins. Traditionally, degradation by this pathway
has been thought to be nonspecific, but there is growing
evidence that some intracellular proteins can be specifically
targeted by the lysosome for degradation.53 A second proteolytic pathway involves Ca2-dependent proteases (eg,
calpains). These proteases are believed to play a role in
cytoskeletal reorganization.54 A third intracellular proteolytic system is even more obscure and involves proteolysis
that does not require energy. The specific enzymes involved
and the mechanisms that regulate their activities are
poorly understood, but this category may include metalloproteases and proteases involved in apoptosis. Finally,
there are energy-requiring proteolytic systems. The fourth
and best-described system for muscle proteolysis is the

Peripheral Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

ubiquitinproteasome pathway, which requires ATP and

degrades the bulk of cellular and some membrane
proteins.55
Activation of the ubiquitinproteasome system has been
well established in a wide range of animal models47 and to a
lesser extent in human muscle tissues in association with
diverse illnesses such as cancer,56 sepsis,57 head trauma,58
and AIDS.59 However, the role of the ubiquitinproteasome
system in the wasting process in patients with COPD
has not been established. In most animal models of
cachexia, the genes encoding for different components of
the ubiquitinproteasome system are up-regulated two- to
fourfold during muscle atrophic processes.47 This system is
complex and consists of a highly organized cascade of
enzymic reactions, which select, mark, and degrade proteins
(Figure 49-3).55 Proteins destined for degradation by this
system are first modified by the attachment of a small protein, ubiquitin. Ubiquitin is abundantly expressed in all
higher eukaryotic cells and is one of the most evolutionarily
conserved proteins known. In most cases, ubiquitin is
linked to the substrate protein through an isopeptide bond
between the -amino groups of lysines in the target protein
and the C-terminal glycine of ubiquitin. Cycles of these
reactions link additional ubiquitins to lysines with ubiquitins added previously.55
The conjugation of ubiquitin and protein substrates
involves a series of complex steps. Initially, an ubiquitinactivating E1 enzyme uses ATP to form an E1ubiquitin
thioester adduct with the C-terminal glycine of ubiquitin. A
single E1 enzyme is responsible for ubiquitin activation in
all mammalian cells. After ubiquitin activation, members
of the E2 ubiquitin-carrier protein family (also called
ubiquitin-conjugating enzymes) participate in the transfer
of the activated ubiquitin to protein substrates. In the vast
majority of cases, a member of the E3 ubiquitinprotein ligase family also participates in the conjugation process. The
purpose of the various E3 ubiquitin ligases is to provide
selectivity to the ubiquitination process by serving as docking proteins that bring the substrate protein and the E2

571

carrier protein with activated ubiquitin together. In some

instances, accessory proteins required for ubiquitin conjugation interact with E3 ubiquitin ligases. The E3 ubiquitin ligases are grouped into three major families, on the basis of
structural similarities and the functional classes of substrates that they recognize. These three groups are the HECT
domain ubiquitin ligases, and the two groups comprising
the RING finger ubiquitin ligases, the single-unit and multisubunit enzymes.55 Recently, two groups have identified
new ubiquitin ligases that are expressed specifically and
robustly in wasting muscles of animals in catabolic states.
MuRF1 (muscle RING finger-1) is a single-subunit RING
finger E3 ligase.60 Atrogin-1 (atrophy gene-1),61 also known
as MAFbx (muscle atrophy F-box),60 is an F-boxcontaining
protein that is a member of the family of the multisubunit
E3 ubiquitin ligases.
Clearly, activation of the ubiquitinproteasome system is
necessary for muscle wasting. However, muscle proteolysis
does not directly depend on activation of this system. For
instance, actomyosin complexes and myofibrils are resistant
to degradation by this system.62 In order to undergo ubiquitination and eventually degradation by the proteasome, contractile proteins must be released from the myofibril and
cleaved. One appealing hypothesis is that activation of
proapoptotic proteases that could cleave actomyosin complexes and actin into fragments is necessary to trigger their
degradation by the ubiquitinproteasome system.63 Other
investigators have suggested that the role played by the
Ca2-dependent proteolytic enzyme calpain is a key step
in the release of actin and myosin from the sarcomere.64
It has also been suggested that the oxidation of contractile
proteins as a consequence of muscle oxidative stress
could be one mechanism triggering the ubiquitination and
degradation of myofibril proteins (see below).
Although muscle proteolysis and activation of the
ubiquitinproteasome system are thought to be of the
utmost importance in the development of cachexia in various conditions, the signals that trigger this process seem to
differ from one pathologic state to another. For instance,

FIGURE 49-3 The ubiquitin (Ub)proteasome pathway. Initially, a Ub-activating

enzyme (E1) uses ATP to form an E1Ub
thioester adduct with the C-terminal
glycine of Ub. After Ub activation, members of the Ub-carrier protein family (E2)
participate in the transfer of the activated
Ub to protein substrates such as actin fragment, which is provided by unidentified
proteolytic steps. In the majority of cases,
a member of the Ubprotein ligase family
(E3) also participates in the conjugation
process. When a chain of four or more Ub
molecules is formed, the chain is recognized by the 26S proteasome, and the
substrate protein is degraded into short
peptides.

572

Exercise Physiology

glucocorticoids and low insulin levels are essential for the

enhanced proteolysis and muscle wasting in diabetes,
whereas tumor necrosis factor- (TNF-), prostaglandins,
and glucocorticoids play important roles in muscle wasting
in sepsis and cancer-induced cachexia.22,47 Finally, acidosis
and glucocorticoids have been shown to play important
roles in the muscle cachexia observed in uremic animals.47

INFLAMMATION

AND

OXIDATIVE STRESS

A common finding in different wasting conditions is the

elevated blood levels of proinflammatory cytokines. The role
of these cytokines in the wasting process is based on the
following observations: (1) cultured myoblasts exposed to
TNF- or other cytokines do not undergo normal differentiation65 and (2) muscle cachexia can be induced in
small animals by systemic injection of proinflammatory
cytokines,66 and this can be prevented by inhibiting the
activity of these cytokines67 or their receptors.66 Although
proinflammatory cytokines such as TNF- and interleukin-6
(IL-6) can activate the ubiquitinproteasome pathway, they
do not reduce lean body mass directly. In this regard, the
activation of nuclear factor kappa B (NFB) seems to be a
key intermediate step.68 NFB is a ubiquitous transcription
factor, present in the cytosol in an inactive form when coupled to its natural inhibitor, IB. Inflammatory cytokines
can activate NFB by initiating the degradation of IB by the
proteasome. Free of its inhibitor, NFB can then translocate
into the nucleus, bind to target DNA elements, and regulate
the transcription of several genes coding for inflammatory
and growth molecules. In muscle, NFB can inhibit the
expression of MyoD, which is a transcription factor that is
essential and specific for skeletal muscle differentiation and
repair.65 Direct inhibition of NFB prevents muscle wasting
in animal models.65 The negative action of NFB on muscle
growth and repair is subject to tight counterregulatory
mechanisms. For instance, NFB can also suppress the transcription of the proteasome C3 subunit in muscle cells, thus
blocking muscle protein degradation.69 Interestingly, glucocorticoids exert their catabolic effect by opposing the NFB
proteasome suppression.69
Inflammation may also induce an oxidantantioxidant
imbalance in patients with chronic disorders by providing a
continuous source of oxidative stress,70 which may contribute to poor muscle performance71 and impaired muscle
regeneration because oxidative stress also inhibits myogenic
differentiation.72 It was recently shown that mild oxidative
stress increases protein degradation in skeletal muscle by
causing increased expression of the major components of
the ubiquitinproteasome pathway.73 In addition, skeletal
muscle proteins modified by reactive oxygen species (ROS)
can be easily degraded by the proteasome.74 Interestingly,
antioxidants may prevent muscle wasting in a murine model
of cachexia induced by TNF-.75 Thus, inflammation and
ROS may have interrelated actions and act synergistically in
inducing muscle proteolysis.
COPD is characterized by low-grade systemic inflammation (reviewed by Debigar and colleagues50), which
is often accompanied by low blood levels of anabolic
hormones.43,44,76 Elevated blood levels of IL-6, IL-8, TNF-,

and C-reactive protein in COPD patients have been associated with low muscle mass, increased resting energy expenditure, and unresponsiveness to nutritional interventions,
giving support to the concept that these cytokines play a role
in COPD-associated cachexia. In addition, levels of adhesion
molecules are increased in bronchoalveolar fluids and
plasma of COPD patients in comparison with healthy subjects. The presence of adhesion molecules in the blood is
necessary for the initiation of bronchial inflammatory cell
infiltration. In theory, these adhesion molecules could also
induce inflammatory cell infiltration in other tissues, such
as skeletal muscle, but this has yet to be verified.
Accordingly, it is conceivable that a low-grade and chronic
systemic inflammatory process may participate in the development of peripheral muscle wasting and dysfunction in
COPD76,77 (reviewed by Debigar and colleagues50).
In view of the possible interaction between proinflammatory cytokines and ROS, it is interesting that there is
increased generation of ROS, originating from the contractile muscles, after low-intensity exercise78 and after local
exercise of the quadriceps muscle in patients with COPD.79
As a result, local muscle exercise induces an imbalance
between oxidant and antioxidant defenses in patients with
COPD. Thus, repeated bursts of ROS occurring within the
peripheral muscles of patients with COPD during activities
of daily living may be involved in triggering the cachexic
cascade. Muscle oxidative stress may also reduce muscle
endurance, as suggested by one study that showed an
inverse and significant relationship between markers of
exercise-induced muscle oxidative stress and quadriceps
muscle endurance.79 These findings support the role of cytotoxic oxidant and oxidative stress in the development of
muscle fatigue and altered endurance capacity in patients
with COPD. Indeed, muscle oxidative stress causes noticeable damage to myocyte organelles, DNA, proteins, and
lipids and results in excessive rises in intracellular free Ca2
level, mitochondrial dysfunction, and bioenergetic enzyme
down-regulation.71

DECREASED ANABOLISM
Although increased catabolism is a hallmark of muscle wasting, there is also support for the hypothesis that anabolic
factors are equally important for muscle mass homeostasis.
A mechanistic link between anabolic factors and the maintenance of muscle mass is emerging.76 For instance, it was
recently demonstrated that insulin and insulin-like growth
factors (IGFs) stimulate myofibril synthesis.80 Conversely,
insulin and IGFs can decrease protein degradation by reducing the activity of the ubiquitinproteasome pathway.81,82
Interestingly, proinflammatory cytokines can exert a suppressive action on IGF-1 by up-regulating the expression of
its circulating inhibitor, insulin-like growth factor binding
protein-1.83 This indicates that there is a close relationship
between the catabolic and anabolic pathways. Other factors
regulating muscle growth, such as myostatin and myogenin,
have been recently identified, and their role in wasting
disorders is currently being investigated.84,85
Concurrently with the low-grade systemic inflammation,
patients with COPD also show a higher prevalence of low

Peripheral Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

plasma levels of testosterone44,76 and IGF-143 than healthy

subjects of a similar age. The clinical relevance of this finding remains to be elucidated as correlations between body
weight or muscle mass and plasma levels of these hormones,
taken individually, are weak,44,76 and supplementation with
anabolic steroids39 or growth hormone86 had only a modest
effect on lean mass and functional status. However, a significant relationship has been described between IL-6/DHEAS
(dehydroepiandosterone, DHEAS sulfate) ratio and midthigh
muscle cross-sectional area in patients with COPD, supporting the concept that the balance between catabolic and anabolic factors is more relevant to muscle wasting than either
category of factors taken individually.76 This finding also
suggests that there is an intimate relationship between the
catabolic and anabolic pathways in regulating muscle mass.

NUTRITIONAL IMBALANCE
Increased total daily and resting energy expenditure is
common in patients with COPD and could contribute to
body weight and muscle mass loss.87,88 In many patients, the
greater energy expenditure is compensated for by increases
in caloric intake, so that body weight is maintained.
However, this adaptation is progressively lost in patients
with severe COPD, as indicated by Schols and colleagues,
who reported a decrease in caloric intake with increasing
severity of airflow obstruction.88 Although nutritional
imbalance may play a role in muscle wasting in some
patients, the absent or modest improvement in peripheral
muscle function associated with nutritional supplementation suggests that a negative energetic balance is not the
primary mechanism of muscle wasting in most cases.46

HYPOXEMIA
In healthy subjects, chronic hypoxia decreases muscle mass,
lowers the oxidative capacity of skeletal muscle, and reduces
the cross-sectional area of type I fibers.89 In keeping with
this, a positive correlation between the arterial partial pressure of oxygen (PaO2) and percentage of type I fibers in the
vastus lateralis muscle has been reported in patients with
COPD.40 Although such a relationship should be interpreted
with caution, since hypoxemia only occurs in patients with
advanced disease and severe functional impairment, it raises
the possibility that chronic hypoxemia may play a role in
patients with low resting PaO2 or in those with repeated oxygen desaturation occurring during sleep and/or exercise.90
Hypoxemia may also contribute to wasting in COPD by
decreasing anabolic hormone levels91 and increasing proinflammatory cytokine levels.92 The presence of hypoxemia is
also associated with the generation of ROS, which contribute to oxidative stress.78 Overall, hypoxemia may contribute to wasting by shifting the balance between anabolic
and catabolic factors in favor of the latter.

CHRONIC INACTIVITY

AND

DECONDITIONING

Chronic inactivity leading to muscle deconditioning is the

most often quoted cause of peripheral muscle dysfunction in
COPD. It is a common observation that patients with COPD
often reduce their level of activity to avoid the dyspnea that
ambulation engenders. Furthermore, the similarity between

573

the histochemical and enzymic muscle changes associated

with chronic inactivity in healthy humans and those
reported in patients with COPD5 is another indication that
muscle deconditioning is likely in COPD. The different
degrees of activation of the lower limb muscles and upper
limb and diaphragmatic muscles may be responsible for the
different levels of abnormalities in these three muscle
groups.8,20 In comparison with lower limb muscles, those of
the upper limb probably remain more active in daily living,
explaining why their function is relatively maintained.8,19
Furthermore, in COPD, the pectoralis major and latissimus
dorsi muscles may also act as accessory inspiratory muscles,
another potential source of stimulation.93 The level of activation of the diaphragm is also greater than that of the lower
limb muscles in COPD, and the chronic increase in work of
breathing faced by the diaphragm is, in fact, a continuous
training stimulus. The increased proportion of type I fibers
in the emphysematous diaphragm is likely to represent
an adaptation to training, reinforcing the role of deconditioning in peripheral muscle dysfunction in these individuals.20 Finally, the improvement in skeletal muscle oxidative
capacity observed after training also supports a role for
deconditioning.38

SYSTEMIC VERSUS LOCAL FACTORS

MUSCLE DYSFUNCTION

IN

PERIPHERAL

The finding that diaphragmatic function is preserved or even

better than expected in COPD20,21,94 is inconsistent with the
possibility that muscle wasting is entirely due to systemic factors. Therefore, local factors must be involved in the development of peripheral muscle cachexia in COPD. The most
obvious candidate is decreased level of activity. Inactivity may
increase the activity of the ubiquitinproteasome pathway95
and reduce the production of IGF-1, one of the main muscle
growth factors.96 More recently, IGF-2, but not IGF-1, was
shown to be down-regulated in muscle atrophy induced by
weightlessness in rats.97 Peripheral muscles and the liver are
major sources of IGF.96 Because of differences in the level of
muscle activation, we therefore speculate that IGF-1 and
IGF-2 are down-regulated in the vastus lateralis muscle but
not in the diaphragm in patients with COPD. In contrast to
inactivity, exercise training should improve the balance
between catabolism and anabolism by increasing the levels
of muscle growth factors.
Other local factors, yet to be identified, are likely to be
involved in muscle wasting, as indicated by the marked
modifications in the myosin heavy-chain profile of the vastus lateralis muscle in patients with COPD in comparison
with healthy subjects, despite modest differences in physical
fitness.98 Perhaps the most provocative observation in this
regard is the decreased hindlimb muscle oxidative capacity
found in the emphysematous hamster despite there being no
reduction in the level of activity in comparison with control
animals.99 We can only speculate about the factors that
could also contribute at the local level to the induction of
muscle wasting. The results of some animal studies suggest
that muscle acidosis may be involved in protein degradation.47 This may be relevant to patients with COPD,
in whom mild exercise, such as that performed in daily

574

Exercise Physiology

FIGURE 49-4 Schematic representation

of the possible mechanisms of cachexia
in chronic obstructive pulmonary disease. Growth factors such as insulin-like
growth factor-1 (IGF-1) and MyoD exert
their anabolic effects by activating
myofibril synthesis. Myofibrillar proteins
are marked for degradation by ubiquitin
(Ub) and are then processed through
the 26S proteasome. This protein degradation pathway can be activated by muscle inactivity. Proinflammatory cytokines
such as tumor necrosis factor (TNF)
(shown here), interleukin-1 (IL-1), and
IL-6 exert their catabolic effects by
activating nuclear factor kappa B
(NFB), which can enter the nucleus
after dissociating from its inhibitor (IB).
One catabolic action of NFB is to
repress the gene expression of MyoD.
Proinflammatory cytokines may also
activate the ubiquitinproteasome pathway. A reasonable hypothesis is that
systemic (TNF, growth factors) as well as
local (inactivity, acidosis) factors interact
in the development of cachexia. IGFR
insulin-like growth factor receptor;
MHC myosin heavy chain; TNFR I and
II TNF receptors I and II. Reproduced
with permission from Debigar R et al.50

living, induces early and exaggerated muscle acidosis in

comparison with healthy subjects.17 As indicated above,
ROS may act locally to trigger muscle wasting. The exciting
hypothesis that muscle wasting could occur without a
decrease in muscle activation will be extremely difficult to
show in humans, in whom the level of physical activity
cannot be adequately controlled.

APOPTOSIS
The results of recent studies on apoptosis suggest that an
increased frequency and/or intensity of this phenomenon
could be responsible for the segmental loss of muscle mass
in many different conditions, such as inactivity, aging, and
congestive heart failure (reviewed by Sandri100). Although
similar findings have also been obtained in COPD,101 it is
not clear how apoptosis is triggered in skeletal muscle.
Death signals originate in some foci and are translated
into apoptotic events through the cell by mitochondriarelated pathways. It has been suggested that apoptosis
occurs in only part of the multinucleated muscle fiber as a
segmental process in order to maintain the right cytoplasm/nucleus ratio.100 Perhaps, in atrophying muscle,
apoptosis acts as a regulatory mechanism, maintaining a
vital degree of function in the affected muscle group.
A reasonable integrative hypothesis is that cachexia in
COPD is the result of an interplay of systemic factors
(eg, cytokines, growth factors) that, although not remarkably elevated, may synergize with local factors (eg, inactivity, ROS, acidosis), leading to a disequilibrium between
anabolism and catabolism.50 A simplified but useful
schematic representation of the cellular mechanisms of

muscle wasting in COPD is given in Figure 49-4. Further

studies are warranted to determine the relative importance
of all the potential factors involved in this complex
process.

CORTICOSTEROIDS
Muscle wasting and weakness characterize steroid-induced
myopathy and preferentially affect type IIb fibers.102 The
potential role of corticosteroids in the development of muscle weakness should not be overlooked in some individuals
submitted to chronic or even intermittent systemic corticosteroid treatment.25,102 In patients with COPD, subtle muscle
weakness may appear with low doses of corticosteroids
(10 mg/day), perhaps because of greater susceptibility to
the development of corticosteroid-induced myopathy.25

TREATMENT OF PERIPHERAL MUSCLE

DYSFUNCTION IN COPD
The treatment of peripheral muscle dysfunction is likely to
remain suboptimal as long as our understanding of this
problem is incomplete. Because the etiology of peripheral
muscle dysfunction in COPD appears to be multifactorial,
one isolated therapeutic strategy is unlikely to completely
resolve the problem. A global approach, with correction of
all possible contributing factors, should have a better chance
of success.
Although no cure is available for muscle wasting in
COPD patients, it is important to recognize the potential
therapeutic consequences of peripheral muscle wasting.
Gains in muscle mass and strength have been associated with

Peripheral Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

better exercise tolerance and survival.103 Thus, improving

peripheral muscle function is an important therapeutic target
in patients with COPD.

EXERCISE TRAINING
Probably the best available therapeutic modality for increasing and/or preserving muscle mass is exercise training,
which has been shown to increase muscle mass, strength,
and aerobic capacity.38,104,105 Several studies have indicated
that patients with severe COPD can sustain the necessary
training intensity and duration for skeletal muscle adaptation to training to occur.11,38,106 After 12 weeks of leg-cycling
exercise, increases were found in the activity of two
mitochondrial enzymes (Figure 49-5), type I fiber size of
the vastus lateralis muscle, and capillary density.11,38 As a
consequence of the improvement in muscle oxidative capacity with training, changes in muscle metabolism also
occur, leading to a reduction in lactic acid efflux during
exercise.105 Other investigators have reported increased
quadriceps muscle endurance during voluntary contractions
after 3 weeks of endurance training.107 Strength training
also appears to be worthwhile in patients with COPD108
as this type of training has more potential to improve muscle mass and strength than does aerobic training.104 In
addition, strength training causes less dyspnea during
the exercise period, making this strategy easier to tolerate
by patients with severe COPD than aerobic training.108

NUTRITIONAL INTERVENTION
Nutritional support has been used with the hope that
restoring nutritional balance will increase body weight,
muscle mass and, ultimately, functional status. Comparison
between studies is difficult because of the variety of nutritional interventions (reviewed by Ferreira and colleagues46).
Weight gain can be achieved with oral or enteral nutritional
supplementation for 2 to 12 weeks, although the results are

CS

HADH

35

12
10

(mol/min/g)

30
8
*

25

6
4

20
2
15

0
PRE

POST

PRE

POST

FIGURE 49-5 Individuals values for the activity of citrate synthase (CS) and 3-hydroxyacyl-CoA-dehydrogenase (HADH) in 11
patients with COPD before and after 12 weeks of exercise training.
These values increased significantly after training. *p .05,
p .01. Reproduced with permission from Maltais F et al.38

575

often modest and inconsistent. Patients in whom body

weight increases following a nutritional intervention show a
somewhat better prognosis than those in whom this
intervention does not modify body weight.103 However,
it is unclear whether the survival advantage in the responders is related to the gain in body weight per se or
simply reflects the presence of more favorable patient
characteristics.
Typically, the increase in body weight resulting from
nutritional supplementation is due to an increase in fat, with
there being little or no increase in muscle mass.39 It is therefore not surprising that the magnitude of improvement in
muscle strength and functional status following nutritional
supplementation is often disappointing. There are also
important limitations to aggressive nutritional intervention
in patients with severe COPD. Gastrointestinal symptoms,
such as bloating, early satiety, meal-related oxygen desaturation, and postprandial dyspnea, are common side effects.109
Despite the lack of strong evidence for beneficial effects of
nutritional intervention on muscle function, it is nevertheless advisable to restore a positive energetic balance for
patients with low body weight. The first step in achieving
this goal is dietetic counseling.109

ANABOLIC HORMONE SUPPLEMENTATION

The results of anabolic steroid39,110 and growth hormone86
supplementation have been disappointing so far. However,
the doses used were probably subtherapeutic, and further
studies are needed to determine optimal dosages for these
anabolic hormones. The use of these drugs should also be
studied in conjunction with exercise training as synergy may
be observed.111

OXYGEN THERAPY
Although short-term oxygen therapy enhances exercise
tolerance and muscle aerobic metabolism in hypoxemic
patients with COPD,16 little is known of the effects of
long-term oxygen therapy on muscle function. Six to nine
months of home oxygen therapy has been shown to facilitate
the formation of muscle ATP but does not appear to improve
skeletal muscle enzyme activity.12 It seems possible that
long-term oxygen supplementation might allow an
increased level of activity and therefore improved muscle
function. This possibility deserves to be investigated.

NOVEL THERAPEUTIC STRATEGIES

Based on our current knowledge of muscle homeostasis,
several novel therapeutic avenues can be proposed to reverse
the wasting. One way to intervene is to increase protein synthesis with the use of growth factors such as IGF-1, which
can suppress ubiquitinproteasome activities81 and induce
hypertrophy.80 Novel forms of nutritional intervention,
involving branched amino acid supplementation (leucine,
isoleucine, and valine), are of interest as they may inhibit
proteolysis in skeletal muscle by acting as a negative feedback regulator of the lysosomal proteolytic system and by
decreasing ubiquitinproteasome system gene expression.112
In rats, clenbuterol, a 2-adrenergic agonist, normalizes protein breakdown and prevents skeletal muscle wasting.113

576

Exercise Physiology

However, equivocal results have been obtained with this

drug in humans.114 The efficacies of new antiinflammatory
drugs, such as cytokine inhibitors or muscle-specific proteasome inhibitors, alone or together, in blocking muscle proteolysis and increasing muscle mass are likely to be
evaluated in the near future.115 Finally, antioxidants could
also represent another promising therapeutic target. Clearly,
research on muscle wasting in patients with COPD and
other chronic diseases will help identify new therapeutic
strategies for this important problem that can reverse its
adverse clinical effects.

CONCLUSION
Modern medicine faces the challenge of improving the care
of patients with chronic diseases such as COPD. Despite all
the efforts of preventive medicine, the burden of COPD is
expected to increase in the coming decades. Unless a cure
for the disease is found, physicians will have to deal with
the systemic consequences of COPD. It will therefore be
important to better address the problem of peripheral muscle dysfunction as an appropriate treatment for this condition should result in a better life for our patients in terms of
both quality and duration.

ACKNOWLEDGMENT
The research discussed in this chapter was supported by
CIHR grant no. MOP-53135.

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