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Journal ArticleDOI

Pathophysiology of muscle dysfunction in COPD

01 May 2013-Journal of Applied Physiology (American Physiological Society)-Vol. 114, Iss: 9, pp 1222-1234
TL;DR: The present review examines the current state of the art of the pathophysiology of muscle dysfunction in COPD and finds that deconditioning seems to play a key role in peripheral muscle dysfunction.
Abstract: Muscle dysfunction often occurs in patients with chronic obstructive pulmonary disease (COPD) and may involve both respiratory and locomotor (peripheral) muscles. The loss of strength and/or endurance in the former can lead to ventilatory insufficiency, whereas in the latter it limits exercise capacity and activities of daily life. Muscle dysfunction is the consequence of complex interactions between local and systemic factors, frequently coexisting in COPD patients. Pulmonary hyperinflation along with the increase in work of breathing that occur in COPD appear as the main contributing factors to respiratory muscle dysfunction. By contrast, deconditioning seems to play a key role in peripheral muscle dysfunction. However, additional systemic factors, including tobacco smoking, systemic inflammation, exercise, exacerbations, nutritional and gas exchange abnormalities, anabolic insufficiency, comorbidities and drugs, can also influence the function of both respiratory and peripheral muscles, by inducing modifications in their local microenvironment. Under all these circumstances, protein metabolism imbalance, oxidative stress, inflammatory events, as well as muscle injury may occur, determining the final structure and modulating the function of different muscle groups. Respiratory muscles show signs of injury as well as an increase in several elements involved in aerobic metabolism (proportion of type I fibers, capillary density, and aerobic enzyme activity) whereas limb muscles exhibit a loss of the same elements, injury, and a reduction in fiber size. In the present review we examine the current state of the art of the pathophysiology of muscle dysfunction in COPD.

Summary (3 min read)

Introduction

  • Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain; and 4Fundació Investigació Sanitària Illes Balears , Mallorca, Spain Submitted 9 August 2012; accepted in final form 13 March 2013 Gea J, Agustí A, Roca J. Pathophysiology of muscle dysfunction in COPD.
  • The loss of strength and/or endurance in the former can lead to ventilatory insufficiency, whereas in the latter it limits exercise capacity and activities of daily life.
  • Additional systemic factors, including tobacco smoking, systemic inflammation, exercise, exacerbations, nutritional and gas exchange abnormalities, anabolic insufficiency, comorbidities and drugs, can also influence the function of both respiratory and peripheral muscles, by inducing modifications in their local microenvironment.
  • Under all these circumstances, protein metabolism imbalance, oxidative stress, inflammatory events, as well as muscle injury may occur, determining the final structure and modulating the function of different muscle groups.

MUSCLE DYSFUNCTION: DEFINITION AND MAIN PHYSIOLOGICAL CONCEPTS

  • Muscle dysfunction is defined as the loss of at least one of the two main muscle properties: strength and endurance (64).
  • Muscle endurance is more difficult to assess but can be evaluated using tests that involve the use of either progressive loads or a continuous submaximal load until exhaustion.
  • In any case, both strategies are useful to explore this functional property either in peripheral or respiratory muscles (28, 156, 157).
  • Moreover, muscle fatigue might also be considered as acute or chronic depending on whether its development occurs suddenly or gradually over time (53).
  • These indicators revert to a physiological level under resting conditions.

RESPIRATORY MUSCLES

  • Inspiratory muscles expand the thoracic cage generating the negative alveolar pressure that results in inspiratory flow.
  • As already mentioned, respiratory muscle dysfunction in COPD is caused by the combination of different local and systemic factors (Fig. 1).
  • On the one hand, muscles are facing an increase in mechanical ventilatory loads.
  • Further, these factors (and perhaps some others that still remain unidentified) induce a series of cellular and molecular events within the muscles that can have a negative effect on their structure and function.
  • Importantly, some of these modifications are not restricted to the diaphragm since they have also been found in other respiratory muscles (85, 104, 163).

LOCOMOTOR MUSCLES

  • Functional impairment of limb muscles (often referred to as peripheral muscles) is present in about one-third of COPD patients, having important clinical consequences for them, since it is associated with low exercise tolerance (72), a reduction in quality of life (132), greater use of health care resources (40) and higher mortality (191).
  • Most of these studies have been performed in lower limb muscles, especially the quadriceps (16, 73, 79), although there are also some studies in upper limb muscles (72, 156).
  • Interestingly, the decline in limb muscle strength, and particularly that of the quadriceps muscle, has been shown to be two to four times faster in COPD patients than in healthy individuals (79).
  • First is the fact that functional and structural impairment appears to be more pronounced in lower limb than in upper limb muscles (63, 64, 76), which are believed to be less severely exposed to the consequences of a reduction in physical activity (63).
  • This is the case, for instance, of fiber atrophy, decreased percentage of aerobic fibers, reductions in the activity of oxidative enzymes and capillary density, as well as the presence of oxidative stress and early lactate release during exercise (66, 144).

SYSTEMIC FACTORS INVOLVED IN MUSCLE DYSFUNCTION

  • In the present review, “factors” have been defined as those elements of systemic origin that may influence muscle function in COPD patients.
  • Whereas the former can act as a signal for the expression of inflammatory mediators (65), the latter (along with other factors such as a reduced blood flow, hypoxia and contractile activity) can modulate the level of ROS production and therefore of oxidative stress (65, 190) (Fig. 2).
  • Moreover, changes in muscle mass and muscle dysfunction are also frequent in highly prevalent comorbidities of COPD such as chronic cardiac failure, diabetes, and cancer (35, 160, 188).
  • Moreover, exacerbations appear to further contribute to muscle wasting and dysfunction (142, 185, 203), probably as a result of the increased systemic inflammation and oxidative stress (1, 34, 185), infection, marked physical inactivity (142), and negative energy imbalance (32, 82, 200) that characterize these episodes, as well as some of the drugs used in their treatment (39).

SKELETAL MUSCLE FINDINGS AND LOCAL MECHANISMS

  • A significant number of studies have investigated the metabolic and structural changes that occur in skeletal muscles.
  • Since the findings reported in the latter have already been mentioned in a previous section this part will focus on peripheral muscles.
  • It should be noted that some of the changes found in the quadriceps and tibialis anterior muscles such as the decrease in the proportion of type I fibers are more pronounced in patients with more severe COPD (71), while others can be seen even in mild-to-moderate stages of the disease (10).

FUTURE PERSPECTIVES

  • Current evidence emerging from a great deal of investigations conducted in the last two decades has clearly demonstrated the contribution of different local and systemic factors and several molecular and cellular mechanisms to muscle dysfunction in COPD.
  • A complete and comprehensive view of its etiology is still lacking.
  • The incorporation of new technical and conceptual advances in basic sciences as well as new perspectives such as those coming from the bioinformatics and bioengineering fields might help investigators working on this specific arena to address questions from complementary points of view.
  • This should lead to new therapeutic and even prophylactic approaches for the management of COPD muscle dysfunction.

CONCLUSIONS

  • Muscle dysfunction is a common manifestation among COPD patients.
  • Both local and systemic factors play a relevant role in its pathogenesis.
  • Among the former, mechanical imbalance due to increased preloads and hyperinflation constitute the main factor that contributes to respiratory muscle dysfunction, whereas deconditioning due to reduced physical activity is the main driver of peripheral muscle dysfunction.
  • As to the effects of the systemic contributors, tobacco, nutritional and gas exchange abnormalities, exercise, exacerbations, systemic inflammation, and drugs are believed to also contribute to muscle dysfunction in patients with COPD.
  • All these factors are able to modify the local microenvironment of the muscle, resulting in protein imbalance, injury, local inflammation, and oxidative stress, among other phenomena, subsequently determining muscle structure and function.

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HIGHLIGHTED TOPIC Muscle Dysfunction in COPD
Pathophysiology of muscle dysfunction in COPD
Joaquim Gea,
1,2
Alvar Agustí,
2,3,4
and Josep Roca
2,3
1
Servei de Pneumologia, Hospital del Mar-IMIM, Universitat Pompeu Fabra, Barcelona, Spain;
2
CIBER de Enfermedades
Respiratorias (CIBERES), ISCIII, Bunyola, Spain;
3
Servei de Pneumologia, Institut del Tòrax. Hospital Clínic-IDIBAPS,
Universitat de Barcelona, Barcelona, Spain; and
4
Fundació Investigació Sanita
`
ria Illes Balears (FISIB), Mallorca, Spain
Submitted 9 August 2012; accepted in final form 13 March 2013
Gea J, Agustí A, Roca J. Pathophysiology of muscle dysfunction in COPD.
J Appl Physiol 114: 1222–1234, 2013. First published March 21, 2013;
doi:10.1152/japplphysiol.00981.2012.—Muscle dysfunction often occurs in pa-
tients with chronic obstructive pulmonary disease (COPD) and may involve both
respiratory and locomotor (peripheral) muscles. The loss of strength and/or endur-
ance in the former can lead to ventilatory insufficiency, whereas in the latter it
limits exercise capacity and activities of daily life. Muscle dysfunction is the
consequence of complex interactions between local and systemic factors, frequently
coexisting in COPD patients. Pulmonary hyperinflation along with the increase in
work of breathing that occur in COPD appear as the main contributing factors to
respiratory muscle dysfunction. By contrast, deconditioning seems to play a key
role in peripheral muscle dysfunction. However, additional systemic factors,
including tobacco smoking, systemic inflammation, exercise, exacerbations, nutri-
tional and gas exchange abnormalities, anabolic insufficiency, comorbidities and
drugs, can also influence the function of both respiratory and peripheral muscles, by
inducing modifications in their local microenvironment. Under all these circum-
stances, protein metabolism imbalance, oxidative stress, inflammatory events, as
well as muscle injury may occur, determining the final structure and modulating the
function of different muscle groups. Respiratory muscles show signs of injury as
well as an increase in several elements involved in aerobic metabolism (proportion
of type I fibers, capillary density, and aerobic enzyme activity) whereas limb
muscles exhibit a loss of the same elements, injury, and a reduction in fiber size. In
the present review we examine the current state of the art of the pathophysiology
of muscle dysfunction in COPD.
respiratory muscles; limb muscles; muscle dysfunction; hyperinflation; decondi-
tioning; muscle wasting; exercise; exacerbations
MUSCLE STRUCTURE AND FUNCTION are frequently abnormal in
patients with chronic obstructive pulmonary disease (COPD)
(5, 66, 123). This common systemic manifestation can have
direct clinical consequences among patients since respiratory
muscles are needed for achieving an appropriate level of
alveolar ventilation, whereas lower limb muscles are essential
for daily life activities. In fact, several studies have shown that
muscle dysfunction reduces both the health-related quality of
life and the life expectancy of COPD patients (118, 158, 191).
The present review is to a great extent an introduction to eight
other minireviews of the highlighted topic on COPD muscle
dysfunction. In those reviews, the most relevant biological
contributors to muscle dysfunction in COPD will be exten-
sively discussed. Therefore, in the following sections we will
1) discuss its definition, principal physiological concepts, and
factors involved in its pathogenesis; and 2) review from a
general perspective the main clinical, cellular, and molecular
mechanisms that contribute to dysfunction in both respiratory
and locomotor muscles.
MUSCLE DYSFUNCTION: DEFINITION AND MAIN
PHYSIOLOGICAL CONCEPTS
Muscle dysfunction is defined as the loss of at least one of
the two main muscle properties: strength and endurance (64).
The former corresponds to the capacity to develop a short
maximal contractile effort, whereas the latter is characterized
by the ability to maintain a submaximal exercise load through-
out a more prolonged period of time. Strength mainly depends
on muscle mass (which in turn is determined by the size and
density of the fibers), muscle resting length, velocity of short-
ening, and the recruitment pattern of motor units (87). Con-
versely, endurance is mainly determined by the coordination of
all different elements involved in oxygen delivery and utiliza-
tion by the muscle (type I fiber proportion, capillary density,
and oxidative enzyme activities, among others) (5). Muscle
strength can be easily assessed by means of its direct determi-
Address for reprint requests and other correspondence: J. Gea, S. Pneumo-
logia, Hospital del Mar-IMIM, Pg. Marítim 27, E-08003 Barcelona, Spain
(e-mail: jgea@parcdesalutmar.cat).
J Appl Physiol 114: 1222–1234, 2013.
First published March 21, 2013; doi:10.1152/japplphysiol.00981.2012.
Review
8750-7587/13 Copyright
©
2013 the American Physiological Society http://www.jappl.org1222

nation using dynamometry (limb muscles) or the measurement
of maximal respiratory pressures (respiratory muscles) both in
clinical and experimental settings (5, 179, 208). In general
maximal efforts are obtained through voluntary maneuvers but
the use of either electrical or magnetic stimulation avoids
relying on the subject’s full collaboration (117, 120). Muscle
endurance is more difficult to assess but can be evaluated using
tests that involve the use of either progressive loads or a
continuous submaximal load until exhaustion. It is worth
noting that in this latter modality the outcome variable is time,
which is most appropriate to reflect endurance. In any case,
both strategies are useful to explore this functional property
either in peripheral or respiratory muscles (28, 156, 157).
The concept of muscle dysfunction includes the presence of
at least one of the following conditions: weakness, reduced
endurance, and fatigue. Either muscle weakness, characterized
by a reduction in muscle force, or reduced muscle endurance
are relatively stable situations, which can be easily identified
(see above). The restoration of either muscle force or endur-
ance requires medium- or long-term therapeutic measures,
including strength training and nutritional interventions, and
endurance training, respectively (5). Conversely, muscle fa-
tigue implies a temporary loss of the contractile function that
can be reversed by rest. Muscle fatigue can be partial or
complete, involving in this case the total inability to further
maintain the effort. Moreover, muscle fatigue might also be
considered as acute or chronic depending on whether its
development occurs suddenly or gradually over time (53).
However, the concept of chronic fatigue is controversial and
has lost support in recent years. Fatigue can also be divided
into central and peripheral, depending on whether its origin lies
on the nervous system or muscle structures, respectively (53).
Muscle fatigue can be identified through neurophysiological or
mechanical indicators, both revealing the transient inability to
perform a target task. These indicators revert to a physiological
level under resting conditions. Importantly, weakness, reduced
endurance, and fatigue can be present simultaneously in the
same patient. Moreover, a weak muscle will become fatigued
much more easily. Muscle dysfunction in COPD is the end
result of a complex interaction between several factors, which,
in turn, induce many different molecular and cellular events
within the muscle (10, 11, 14, 38, 137, 171). These factors and
their biological consequences are not always equivalent for
respiratory and limb muscles. For this reason, in the following
sections these two muscle groups will be reviewed separately.
RESPIRATORY MUSCLES
Inspiratory muscles expand the thoracic cage generating the
negative alveolar pressure that results in inspiratory flow.
Among them, the diaphragm has been classically considered as
the main inspiratory muscle, at least in healthy and young
subjects breathing under resting conditions. However, when
the ventilatory demands increase as a result of aging, respira-
tory diseases, and/or exercise, other muscles progressively
participate in the breathing effort, becoming even more rele-
vant than the diaphragm (24, 42, 44). In these cases, the
external and parasternal (the interchondral extension of the
internal interosseus) intercostals become major players. The
diaphragm is a dome-shaped muscle, which is composed by
costal and crural parts, acting mainly by expanding the lower
rib cage (41). Whereas the costal part appears to be more
relevant for inspiration, the crural portion also plays a relevant
role in the gastroesophageal function (187). Contraction of
external and parasternal intercostal muscles enlarges mostly
the global chest cross-sectional area, whereas scalenes expand
the upper rib cage. The diaphragm, parasternal intercostals, and
scalenes are considered as primary inspiratory muscles, since
they are phasically recruited with each inspiration. Muscles
that are inactive under normal ventilatory conditions, and are
recruited only upon increased ventilatory demands, are called
accessory muscles. The combined action of inspiratory mus-
cles expanding the thorax and the elastic recoil of the lung
results in a more negative pleural pressure, which is transmit-
ted to the alveolar region and causes the entry of air into the
lungs.
Although expiration is normally a passive process, second-
ary to the relaxation of the inspiratory muscles, air exhalation
can be facilitated by the contraction of other muscle groups,
including those of the abdominal wall and the internal inter-
costals. This action along with the air trapping that may
concomitantly occur appears to be involved in the increase of
dyspnea and lack of bronchodilator response shown by some
COPD patients (111, 139).
The function of respiratory muscles, which is frequently
impaired in COPD patients (165, 203), may contribute to
hypercapnic respiratory failure and exercise limitation. Respi-
ratory muscle dysfunction has been associated with an in-
creased risk for repeated hospital admissions (203) and prema-
ture death (158). As already mentioned, respiratory muscle
dysfunction in COPD is caused by the combination of different
local and systemic factors (Fig. 1). On the one hand, muscles
are facing an increase in mechanical ventilatory loads. Since
COPD is mainly characterized by airflow limitation, as well as
pulmonary hyperinflation and increased compliance, this will
have important mechanical consequences. Different elastic
(derived from changes in the thorax wall and lung paren-
chyma), resistive (caused by air passage through the narrowed
airways) and threshold (such as that derived from the intrinsic
positive end-expiratory pressure, PEEPI) loads increase in
patients (53, 65, 66), thus imposing an increased work of
breathing and overloading respiratory muscles (53, 166). On
the other hand, static pulmonary hyperinflation modifies thorax
geometry, shortening the diaphragmatic length (166, 182), a
situation that can be even accentuated by dynamic pulmonary
hyperinflation. In this regard, the diaphragm is displaced away
from its optimal length to generate force, and its costal and
crural parts probably become less coordinated (110). All these
factors lead to a mismatching between mechanical require-
ments of the respiratory system and functional capacity of the
ventilatory muscles, as well as between the metabolic demands
and the energy supply to these muscles (66, 204).
Besides local influences, a number of systemic factors may
also negatively affect this already adverse scenario in the
respiratory muscles. These systemic factors, which can also be
present in other muscle groups, include systemic inflammation,
pulmonary gas exchange and nutritional abnormalities, the
systemic consequences of concomitant disorders, and the direct
effects of tobacco and some drugs used in the treatment of
COPD patients, such as systemic steroids (13, 39, 43, 180) (see
next sections). All in all, this leads to more metabolic derange-
ments superimposed on top of the mechanical factors discussed
Review
1223Mechanisms of Muscle Dysfunction in COPD Gea J et al.
J Appl Physiol doi:10.1152/japplphysiol.00981.2012 www.jappl.org

above. Further, these factors (and perhaps some others that still
remain unidentified) induce a series of cellular and molecular
events within the muscles that can have a negative effect on
their structure and function. Muscle damage (137), the pres-
ence of local oxidative stress (11, 119) and inflammatory
elements (24), the activation of proteolytic pathways (193), and
even some signs of a true myopathy (for instance the presence
of paracrystalline inclusions) (109), have been described in
respiratory muscles of COPD patients and can jeopardize their
function (Table 1).
Certainly, the diaphragm of hyperinflated COPD patients
develops less force than that of healthy subjects when both
groups are making the effort at their own functional residual
capacity (FRC). However, the situation becomes completely
different if healthy volunteers are forced to increase their lung
volume to similar levels than those of the patients. Then, it has
been shown that the latter group can develop even greater
diaphragmatic force than the former (182). This suggests that
to some extent respiratory muscles undergo a beneficial adap-
tation in COPD that coexists with the negative scenario that has
been described in previous paragraphs. It is believed that this
adaptation also derives from the increase in mechanical loads
that occurs in the respiratory system of COPD patients, which
would emulate muscle training. The molecular and cellular
changes that are believed to be induced by this “training effect”
in the diaphragm of COPD patients include shorter sarcomeres
(136), increases in the proportion of myosin heavy chain I
(MyHC-I), type I fibers (45, 103), capillary contacts per fiber
(45), and mitochondrial density (136), and enhanced mitochon-
drial respiratory chain capacity (163, 207).
Whereas changes in sarcomere length would partially coun-
terbalance the negative effects induced by the displacement of
the diaphragm length-tension curve on diaphragmatic force in
COPD patients, the other changes would confer the muscle an
enhanced aerobic capacity. Importantly, some of these modi-
fications are not restricted to the diaphragm since they have
also been found in other respiratory muscles (85, 104, 163).
This is the case of the external intercostal muscle of COPD
patients, which has shown an increased oxidative capacity
in vitro (163), probably related to its higher capillary density
and enhanced activity of different enzymes involved in the
aerobic pathways (85, 163, 172). However, no significant
changes have been consistently found in the proportion of type
I fibers in this muscle. By contrast, in the only study published
so far in which the structure of the parasternal muscles was
analyzed in COPD patients, an increase in the percentage of
type I fibers and MyHC-I was reported (104).
In summary, in patients with COPD many different factors
can influence respiratory muscle structure and function, acting
in opposite directions. A few of them exert clear deleterious
effects, while others may also exert a beneficial influence that
would counterbalance, at least in part, the impact of the former.
Therefore, it can be assumed that respiratory muscles operate
in a sort of delicate balance in COPD. Any additional delete-
rious event taking place in this precarious scenario (i.e., exac-
erbation, exercise) may easily lead to ventilatory failure.
LOCOMOTOR MUSCLES
Functional impairment of limb muscles (often referred to as
peripheral muscles) is present in about one-third of COPD
patients, having important clinical consequences for them,
since it is associated with low exercise tolerance (72), a
reduction in quality of life (132), greater use of health care
resources (40) and higher mortality (191). Numerous studies
have demonstrated the loss of muscle strength that occurs in
the limbs of patients with COPD (16, 72, 73, 79, 156). Most of
these studies have been performed in lower limb muscles,
especially the quadriceps (16, 73, 79), although there are also
some studies in upper limb muscles (72, 156). Interestingly, the
decline in limb muscle strength, and particularly that of the
quadriceps muscle, has been shown to be two to four times
faster in COPD patients than in healthy individuals (79).
Although limb muscle endurance has been less studied than
strength, different studies have shown that this functional
property is also reduced in COPD patients (28, 196, 199). It
should be noted that limb muscle dysfunction may occur even
in individuals exhibiting mild to moderate airway obstruction
(179). Moreover, limb muscle dysfunction is absent in half of
the COPD patients with severe disease (179). This interindi-
vidual heterogeneity for the same level of lung function im-
pairment implies that the latter is not the main factor that
causes muscle dysfunction in COPD patients. There are many
evidences that suggest that a significant role should be attrib-
Leading Factor
Other Factors
Changes in
Ventilatory
Mechanics
Muscle
Deconditioning
RESPIRATORY
MUSCLES
PERIPHERAL
MUSCLES
Genetics
Nutritional status
Anabolism/Catabolism
Gas exchange
Systemic Inflammation
Tobacco
Exacerbations
Exercise
Co-morbidities / Aging
Drugs
Fig. 1. Main factors thought to contribute to respiratory
and/or peripheral muscle dysfunction in chronic obstructive
pulmonary disease (COPD). Pulmonary hyperinflation ap-
pears as the main factor contributing to respiratory muscle
dysfunction, whereas deconditioning seems to play the key
role in limb muscle dysfunction. However, additional sys-
temic factors, such as tobacco smoking, systemic inflamma-
tion, intense exercise, exacerbations, nutritional and gas
exchange abnormalities, anabolic insufficiency, comorbidi-
ties, and drugs also modulate muscle function.
Review
1224 Mechanisms of Muscle Dysfunction in COPD Gea J et al.
J Appl Physiol doi:10.1152/japplphysiol.00981.2012 www.jappl.org

uted to muscle deconditioning (or “detraining”), which would
result primarily from the sedentary lifestyle that frequently
follows the increased breathlessness during exercise that char-
acterizes COPD (Fig. 1) (20, 66). Interestingly, limb muscle
dysfunction can also contribute to a further reduction in phys-
ical activity, generating a vicious circle. Moreover, it has been
shown that maintenance of even a moderate level of physical
activity reduces hospital admissions (59), and is associated
with better functional status (61) and life expectancy (59) in
COPD patients, while it delays lung functional decline and
even COPD risk in smokers (60). Three main arguments
support the key pathogenic role attributed to muscle decondi-
tioning in limb muscle dysfunction. First is the fact that
functional and structural impairment appears to be more pro-
nounced in lower limb than in upper limb muscles (63, 64, 76),
which are believed to be less severely exposed to the conse-
quences of a reduction in physical activity (63). Second, many
of the changes and phenomena reported in peripheral muscles
of COPD patients (this will be reviewed in more detail in other
reviews of the present highlighted topic) are quite similar to
those described in muscle disuse (17, 26, 27). This is the case,
for instance, of fiber atrophy, decreased percentage of aerobic
fibers, reductions in the activity of oxidative enzymes and
capillary density, as well as the presence of oxidative stress and
early lactate release during exercise (66, 144). Third, most of
these findings can be partially reversed by muscle training
(114, 135). However, some other abnormalities such as marked
cachexia or increased muscle oxygen consumption at isocharge
(171) still persist despite training, suggesting the presence of
additional factors that are also involved in the pathogenesis of
peripheral muscle dysfunction in COPD. Those factors are
most probably of systemic nature and presumably include
genetic background, tobacco smoking, aging and comorbidi-
ties, systemic inflammation, exacerbations, intense exercise,
nutritional and gas exchange abnormalities, anabolic/catabolic
hormone imbalance, and the effects of some drugs (5, 66).
SYSTEMIC FACTORS INVOLVED IN MUSCLE DYSFUNCTION
A controversial issue refers to which elements related to
muscle dysfunction in COPD would be considered ethiopatho-
genic factors, and which others should be treated as mecha-
nisms of such a dysfunction or merely as muscle findings. In
this regard, in the present review, “factors” have been defined
as those elements of systemic origin that may influence muscle
function in COPD patients. However, events occurring inside
the muscle tissue, which in turn, may provoke further structural
or biological derangements or even directly alter muscle func-
tion, have been defined as “mechanisms.” Since many of the
systemic factors involved in the impairment of muscle function
will be extensively discussed in the other minireviews of this
Highlighted Topic, in the present review, the different mech-
anisms potentially involved in COPD muscle dysfunction will
be discussed using a rather general approach.
Systemic inflammation. The inflammatory response may lead
to the activation of different cellular pathways that can result in
muscle atrophy and/or muscle dysfunction. This is the case of
apoptosis, autophagy, oxidative stress, and catabolic systems
such as that of the ubiquitin proteasome (62). Furthermore,
certain proinflammatory cytokines can directly inhibit muscle
contraction (161). Systemic inflammation may occur in pa-
Table 1. Main structural and functional findings described in skeletal muscles of COPD patients
Fibers Capillarity Mitochondria
Muscle
Injury
Oxidative
Stress
Local
Inflammation Apoptosis
Protein
Imbalance
Oxidative
Capacity
Contractility
Defect
Respiratory Muscles
Diaphragm Type-I % 1 Density 1 Density 1 Cells , 1 (TUNEL) Present 1 Present
Size 2/ Contacts 1 Inclusions present 11Cytokines 1 (EM) O/G 1/
Abnormal function*
External intercostals Type-I % 2/ Density 1 Density 11NA Cells ⫽⫽(TUNEL) NA 1 Absent
Size Abnormal function Cytokines 1 (EM) O/G 2/
Parasternals Type-I % 1 NA NA NA NA NA NA NA NA NA
Size
External oblique Type-I % 2 NA NA NA NA NA NA NA NA NA
Size
Peripheral Muscles
Quadriceps muscle Type-I % 2 Contacts 2 Density 211Cells 11(TUNEL) Present 2 Not clear
Size 2/ Abnormal function* Cytokines 2/1 (EM) O/G 2
Tibialis anterior NA Density 2 Density 2 Possible NA NA NA NA NA
Contacts 2
Deltoid muscle Type I % NA NA NA NA NA NA NA O/G NA
Size 12
Biceps brachii Type I % 1/ NA NA NA NA NA NA NA O/G NA
Size 2
Other Muscles
Latissimus dorsi Type I % NA Abnormal function NA NA NA NA NA O/G NA
Size 1
COPD, chronic obstructive pulmonary disease; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; EM, electron microscopy (ultrastructural analysis); O/G, oxidative/glycolytic enzyme
ratio; contractility defect: force generation in isolated fibers. NA, no data available; , unchanged; /, or; , coexistence; *, respiratory chain capacity 2 and reactive oxygen species 1.
Review
1225Mechanisms of Muscle Dysfunction in COPD Gea J et al.
J Appl Physiol doi:10.1152/japplphysiol.00981.2012 www.jappl.org

tients with COPD as shown in different reports, in which
increases in blood levels of white cells and different biomark-
ers such as C-reactive protein, fibrinogen, and several proin-
flammatory cytokines have been demonstrated (43, 58). Ini-
tially, it was thought that systemic inflammation found in
COPD derives from that which occurs primarily in the lung,
which would spread later on to the rest of the body through the
bloodstream (“spillover” theory) (183). However, the absence
of correlations between the level of inflammatory markers in
the lung and blood or other organs including muscles, and the
presence of muscle changes preceding pulmonary abnormali-
ties strongly argue against this possibility (13, 66, 183). This
suggests that extrapulmonary manifestations of COPD may
start in parallel to the lung disease, being the direct conse-
quence of the same insults. Another intriguing question is to
elucidate the mechanisms involved in the perpetuation of the
inflammatory response after cessation of the initial stimulus.
Recent evidence seems to indicate that these mechanisms are
probably related to an abnormal immunologic response (19). It
should be noted, however, that not all authors have been able
to find systemic inflammation in stable COPD patients (43, 90,
192). In fact, this situation is much more evident during
exacerbations (90).
Systemic oxidative stress. Reactive oxygen species (ROS)
are a product of the aerobic metabolism and are normally
present in different tissues including muscles. However, when
there is an imbalance between the production of ROS and the
antioxidant systems, oxidative stress occurs leading to delete-
rious changes in different key molecules and tissue damage
(66). Oxidative stress and inflammation are mutually interre-
lated. Whereas the former can act as a signal for the expression
of inflammatory mediators (65), the latter (along with other
factors such as a reduced blood flow, hypoxia and contractile
activity) can modulate the level of ROS production and there-
fore of oxidative stress (65, 190) (Fig. 2). Oxidative stress has
been found not only in the lungs but also in the blood and
muscles of stable COPD patients (10, 11, 155, 167). Moreover,
both exacerbations and exercise can increase plasma and/or
muscle levels of oxidative stress markers (12, 77, 90).
Although the relationships between systemic oxidative
stress and muscle dysfunction are not yet clearly elucidated,
a direct relationship has been found between the level of
oxidative stress within the muscle tissue and muscle func-
tion impairment (11).
Gas exchange abnormalities. Both hypoxia and hypercapnia
may have deleterious effects on muscle function in COPD
patients (2, 94). Muscle hypoxia can be present in such patients
due to the reduction in oxygen delivery to the tissues (141)
derived from their hypoxemia and the frequent coexistence of
anemia (212). Hypoxia may induce systemic inflammation,
oxidative stress, protein imbalance, apoptosis and impaired
muscle regeneration (22, 67, 99, 214), generating a reduction in
muscle mass and targeting different elements involved in the
oxidative capacity of muscles (80, 141). Therefore, it is not
surprising that hypoxia can lead to impaired muscle strength
and endurance in COPD patients (66). Hypercapnia, in turn,
may act in skeletal muscles directly or through inducing a
decrease in extracellular and cellular pH. Whereas hypercapnia
has been shown to induce muscle dysfunction both in normal
subjects and in COPD patients (2, 154), acidosis may induce
impaired muscle proteostasis (balance between protein synthe-
sis and breakdown) (52).
Inefficiency of anabolic hormones. Growth hormone is an
anabolic agent that induces an increase in the production of the
insulin-like growth factor 1 (IGF-1), subsequently promoting
an increment in protein synthesis and inhibition of protein
degradation (54). Therefore, it results in muscle growth and
increases in muscle mass (106). The levels of the growth
hormone can be reduced, normal, or even increased in COPD
patients (112, 176), but its interaction with IGF-I seems to be
altered (33), potentially leading to reductions in muscle mass.
Although exogenous growth hormone increases body weight
and muscle mass in undernourished COPD patients, no clear
effects have been demonstrated in muscle function (23).
Testosterone is a steroid hormone secreted by the gonads
and to a lesser extent by the adrenals that has relevant anabolic
effects. Its levels are much higher in men than in women,
participating in the differential development of their muscle
mass. Testosterone increases the synthesis of muscle structural
proteins, an action that can lead to muscle hypertrophy (21).
Different authors have shown that testosterone levels can be
low in COPD patients, potentially leading to a reduced muscle
mass (91, 100). However, the implications of this hypogonad-
ism on muscle dysfunction are not clear, since either muscle
strength and endurance or exercise capacity appears to remain
unaltered (100). The mechanisms of testosterone deficiency in
COPD remain unclear although aging, hypoxia, smoking, and
steroid therapy might be involved (5, 33).
Comorbidities and aging. With the increase in life expec-
tancy in developed societies, the number of elderly COPD
patients is becoming very high. One of the main causes of
muscle functional impairment in aged populations is sarcope-
nia, characterized by the loss of skeletal muscle mass and
changes in muscle characteristics (fiber atrophy and loss,
Stimuli
- Proinflammatory mediators
- By-products of the Arachidonic acid
- ROS & NO production, Ox
idative/Nitrosative stress
Muscle
Dysfunction
Modifications in structural proteins
Modifications in enzymes
Lipid peroxidation
DNA damage
Tobacco
Exercise
Exacerbations
Abnormal gas exchange
Nutritional abnormalities
Fig. 2. Role and relationships of inflamma-
tion and oxidative stress in skeletal muscle
dysfunction of COPD patients. Factors in-
volved. ROS, reactive oxygen species.
Review
1226 Mechanisms of Muscle Dysfunction in COPD Gea J et al.
J Appl Physiol doi:10.1152/japplphysiol.00981.2012 www.jappl.org

Citations
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Journal ArticleDOI
TL;DR: The addition of long-term NPPV to standard treatment improves survival of patients with hypercapnic, stable COPD when NPPv is targeted to greatly reduce hypercapnia.

580 citations

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TL;DR: A comprehensive approach to COPD prevention will need to address the complexity of COPD and the development of strategies to assess COPD in its early stages are needed.

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Journal ArticleDOI
TL;DR: Full elucidation of the specific roles of the target biological mechanisms involved in COPD muscle dysfunction is still required and will be crucial to adequately tackle with this relevant clinical problem of COPD patients in the near-future.
Abstract: Respiratory and/or limb muscle dysfunction, which are frequently observed in chronic obstructive pulmonary disease (COPD) patients, contribute to their disease prognosis irrespective of the lung function. Muscle dysfunction is caused by the interaction of local and systemic factors. The key deleterious etiologic factors are pulmonary hyperinflation for the respiratory muscles and deconditioning secondary to reduced physical activity for limb muscles. Nonetheless, cigarette smoke, systemic inflammation, nutritional abnormalities, exercise, exacerbations, anabolic insufficiency, drugs and comorbidities also seem to play a relevant role. All these factors modify the phenotype of the muscles, through the induction of several biological phenomena in patients with COPD. While respiratory muscles improve their aerobic phenotype (percentage of oxidative fibers, capillarization, mitochondrial density, enzyme activity in the aerobic pathways, etc.), limb muscles exhibit the opposite phenotype. In addition, both muscle groups show oxidative stress, signs of damage and epigenetic changes. However, fiber atrophy, increased number of inflammatory cells, altered regenerative capacity; signs of apoptosis and autophagy, and an imbalance between protein synthesis and breakdown are rather characteristic features of the limb muscles, mostly in patients with reduced body weight. Despite that significant progress has been achieved in the last decades, full elucidation of the specific roles of the target biological mechanisms involved in COPD muscle dysfunction is still required. Such an achievement will be crucial to adequately tackle with this relevant clinical problem of COPD patients in the near-future.

121 citations

Journal ArticleDOI
TL;DR: It is claimed that body composition and quadriceps muscle strength should be routinely explored in COPD patients in clinical settings, even at early stages of their disease.
Abstract: In the next decade, Chronic Obstructive Pulmonary Disease (COPD) will be a major leading cause of death worldwide. Impaired muscle function and mass are common systemic manifestations in COPD patients and negatively influence survival. Respiratory and limb muscles are usually affected in these patients, thus contributing to poor exercise tolerance and reduced quality of life (QoL). Muscles from the lower limbs are more severely affected than those of the upper limbs and the respiratory muscles. Several epidemiological features of COPD muscle dysfunction are being reviewed. Moreover, the most relevant etiologic factors and biological mechanisms contributing to impaired muscle function and mass loss in respiratory and limb muscles of COPD patients are also being discussed. Currently available therapeutic strategies such as different modalities of exercise training, neuromuscular electrical and magnetic stimulation, respiratory muscle training, pharmacological interventions, nutritional support, and lung volume reduction surgery are also being reviewed, all applied to COPD patients. We claim that body composition and quadriceps muscle strength should be routinely explored in COPD patients in clinical settings, even at early stages of their disease. Despite the progress achieved over the last decade in the description of this relevant systemic manifestation in COPD, much remains to be investigated. Further elucidation of the molecular mechanisms involved in muscle dysfunction, muscle mass loss and poor anabolism will help design novel therapeutic targets. Exercise and muscle training, alone or in combination with nutritional support, is undoubtedly the best treatment option to improve muscle mass and function and QoL in COPD patients.

121 citations


Cites background from "Pathophysiology of muscle dysfuncti..."

  • ...In COPD patients, modifi cations in ventilatory mechanics as a result of static pulmonary hyperinfl ation, which modifi es thorax geometry and shortens the diaphragm length, displace the muscle away from its optimal length to generate the required forces (14)....

    [...]

  • ...Additionally, their respiratory muscles need to overcome the increased work of breathing resulting from the greater elastic, resistive, and threshold inspiratory loads imposed by airfl ow limitation (14)....

    [...]

  • ...Finally, the same abovementioned etiologic factors for the lower limb muscles, may also aff ect, to diff erent degrees, the respiratory muscles in COPD: Cigarette smoke, hypoxia, hypercapnia and acidosis, metabolic derangements, malnutrition, genetics, systemic infl ammation, aging, co-morbidities, concomitant treatments, exacerbations, and reduced physical activity (9,14) (Figure 2A)....

    [...]

  • ...In COPD, despite that the respiratory muscles undergo a positive adaptation (training-like eff ect) that renders them more fatigue-resistant (14,21,38), maximal inspiratory and expiratory pressures (strength) and endurance of these muscles are frequently reduced in the patients (14,19,21–23,39,40) (See following section for specifi c details on the etiology and mechanisms)....

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  • ...In fatigue, specifi c neurophysiological and mechanical parameters are altered, while they return to normality by rest (14)....

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TL;DR: This review aims to summarize the recent findings regarding the role of miRNAs in the airways and lung and emphasise their potential therapeutic roles in pulmonary diseases.

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Cites background from "Pathophysiology of muscle dysfuncti..."

  • ...Peripheral muscle dysfunction is a limiting factor in many COPD patients and is associated with high mortality and poor quality of life (Maltais et al., 2000; Gea et al., 2013)....

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  • ...Peripheral muscle dysfunction is a limiting factor in many COPD patients and is associated with high mortality and poor quality of life (Maltais et al., 2000; Gea et al., 2013) ....

    [...]

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23 Nov 2001-Science
TL;DR: Two genes encode ubiquitin ligases that are potential drug targets for the treatment of muscle atrophy, and mice deficient in either MAFbx orMuRF1 were found to be resistant to atrophy.
Abstract: Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

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"Pathophysiology of muscle dysfuncti..." refers background in this paper

  • ...The proteasome is a cellular structure that degrades proteins (mostly those previously tagged with ubiquitins through different ligases) and peptides (especially those which have been modified by oxidative stress) (18, 133, 162, 173, 186, 197) (Fig....

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30 Apr 2004-Cell
TL;DR: It is shown that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction.

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TL;DR: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.

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01 Jul 2004-Thorax
TL;DR: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.
Abstract: Background: Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. Methods: A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-a (TNF-a), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. Results: Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-a levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). Conclusions: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.

1,672 citations


"Pathophysiology of muscle dysfuncti..." refers background in this paper

  • ...tients with COPD as shown in different reports, in which increases in blood levels of white cells and different biomarkers such as C-reactive protein, fibrinogen, and several proinflammatory cytokines have been demonstrated (43, 58)....

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Journal ArticleDOI
David J. Glass1
TL;DR: Recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems are focused on.

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"Pathophysiology of muscle dysfuncti..." refers background in this paper

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Q1. What contributions have the authors mentioned in the paper "Highlighted topic muscle dysfunction in copd pathophysiology of muscle dysfunction in copd" ?

In the present review the authors examine the current state of the art of the pathophysiology of muscle dysfunction in COPD.