J Appl Physiol 114: 1291–1299, 2013.
First published January 31, 2013; doi:10.1152/japplphysiol.00847.2012.
HIGHLIGHTED TOPIC
Review
Muscle Dysfunction in COPD
Mechanisms of striated muscle dysfunction during acute exacerbations
of COPD
Ghislaine Gayan-Ramirez and Marc Decramer
Respiratory Muscle Research Unit, Laboratory of Pneumology and Respiratory Division, Department of Clinical
and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
Submitted 9 July 2012; accepted in final form 19 January 2013
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Gayan-Ramirez G, Decramer M. Mechanisms of striated muscle dysfunction
during acute exacerbations of COPD. J Appl Physiol 114: 1291–1299, 2013. First
published January 31, 2013; doi:10.1152/japplphysiol.00847.2012.—During acute
exacerbations of chronic obstructive pulmonary disease (COPD), limb and respiratory muscle dysfunction develops rapidly and functional recovery is partial and
slow. The mechanisms leading to this muscle dysfunction are not yet fully
established. However, recent evidence has shown that several pathways involved in
muscle catabolism, apoptosis, and oxidative stress are activated in the vastus
lateralis muscle of patients during acute exacerbations of COPD, while those
implicated in mitochondrial function are downregulated. These pathways may be
targeted in different ways by factors related to exacerbations. These factors include
enhanced systemic inflammation, oxidative stress, impaired energy balance, hypoxia, hypercapnia and acidosis, corticosteroid treatment, and physical inactivity.
Data on the respiratory muscles are limited, but these muscles are undoubtedly
overloaded during exacerbations. While they are also subjected to the same
systemic elements as the limb muscles (except for inactivity), they also face a
specific mechanical disadvantage caused by changes in lung volume during exacerbation. The latter will affect the ability to generate force by the foreshortening of
the muscle (especially for the diaphragm), but also by altering rib orientation and
motion (especially for the parasternal intercostals and the external intercostals).
Because acute exacerbations of COPD are associated with an increase in both
prevalence and severity of generalized muscle dysfunction, and both remain present
even during recovery, early interventions to minimize muscle dysfunction during
exacerbation are warranted. Although rehabilitation may be promising, other
therapeutic strategies such as counterbalancing the adverse effects of exacerbations
on skeletal muscle pathways may also be used.
respiratory muscles; limb muscles; proteolysis; oxidative stress; mitochondria;
striated muscles
(COPD) is complicated by the presence of frequent and recurrent acute exacerbations. According to the global initiative for COPD guidelines
(GOLD) (www.goldcopd.org), an acute exacerbation is defined
as an acute event characterized by a worsening of a patient’s
respiratory symptoms that is beyond normal day-to-day variations, and leads to a change in regular medication (9, 10, 67).
In general, exacerbations become more frequent and more severe
as COPD progresses, although a phenotype of frequent exacerbator present in all GOLD stages (GOLD 1, mild; GOLD 2,
moderate; GOLD 3, severe; GOLD 4, very severe) has been
recently described (36). Patients with frequent exacerbations often
experience impaired quality of life, increased dyspnea, and a
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Address for reprint requests and other correspondence: G. Gayan-Ramirez,
Labo Ademspieren, Onderwijs en Navorsing 1, Herestraat 49 bus 706, B-3000
Leuven, Belgium (e-mail: [email protected]).
http://www.jappl.org
faster decline in lung function over time (25, 41, 71). In addition,
severe exacerbations necessitating hospitalization constitute a risk
for mortality during the hospitalization and the subsequent year (3,
12, 56). Next to their impact on pulmonary function, acute
exacerbations also affect other systems, including skeletal muscles. During the last decade, the impact of exacerbations on
skeletal muscles has been investigated. Most of the data pertain to
lower limb muscle data, whereas data on upper limb muscles and
respiratory muscles are scarce.
SKELETAL LIMB AND RESPIRATORY MUSCLE STRENGTH
DURING ACUTE EXACERBATION
Limb muscles. Quadriceps strength measured on day 3 of
hospitalization was shown to be lower in patients with acute
exacerbation of COPD compared with patients with clinically
stable COPD (16, 74). In addition, quadriceps strength in these
patients decreased by about 5% after 5 days of hospitalization
8750-7587/13 Copyright © 2013 the American Physiological Society
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200
QPT (Nm)
150
100
50
0
3
8
No exercise training
90
Time (days)
Fig. 1. Quadriceps peak torque (QPT, expressed in Newton-meters, Nm) in
patients with COPD at day 3 and day 8 of hospital admission for acute exacerbation and 90 days after exacerbation. Each point represents data for a given
patient. Adapted from (74) Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I, Spruit
MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, Bouillon
R, Decramer M, Thorax 58: 752–756, 2003 with permission from BMJ Publishing Group Limited.
Gayan-Ramirez G et al.
irrespective of body weight and BMI (81). This study in fact
highlighted that the prevalence and severity of muscle dysfunction remained elevated despite clinical stability (82).
Respiratory muscles. During acute exacerbations, the maximal
pressure that can be generated by the respiratory muscles is
reduced, as is the muscle efficiency (ratio of mechanical work
output to the total metabolic cost) for the inspiratory muscles,
especially the diaphragm. Indeed, acute dynamic hyperinflation
further shortens the inspiratory muscles, particularly the diaphragm, and causes functional muscle weakness. Therefore, the
accessory muscles of breathing are maximally recruited (as shown
by maximal activation with electromyographic measurement) and
significant alterations in thoraco-abdominal pathway of motion is
often evident. Patients are also at greater risk for the development
of respiratory muscle fatigue than healthy subjects because the
relative force that these muscles exert for each breath is higher
compared with their maximal capacity (8).
In patients with COPD who develop acute hypercapnic
respiratory failure requiring noninvasive mechanical ventilation, it has been shown that muscle strength of both inspiratory
and expiratory muscles was reduced (62). Even at discharge
from a respiratory intensive care unit after severe, acute exacerbation, more than one-third of these patients still presented
respiratory muscle dysfunction (82) that would require further
care and rehabilitation to restore functional impairment.
ALTERATIONS WITHIN THE MUSCLE DURING
EXACERBATION
Alterations in local gene expression have been addressed
only in the vastus lateralis muscle (Fig. 2). In a first study, Crul
et al. (16) showed that on day 4 of hospitalization, the protein
levels of MyoD, the master regulatory gene for skeletal myogenesis, were reduced in hospitalized patients with COPD
compared with healthy elderly, and they were unchanged in
patients with stable COPD. In addition, the anabolic marker
insulin-like growth factor I (IGF-I) mRNA levels were reduced
in COPD but to a similar extent in stable and hospitalized
patients (16). In addition, the MyoD protein levels were positively correlated with quadriceps force, suggesting a functional
role for MyoD in the observed muscle weakness (16). Similar
alterations in MyoD and IGF-I have been observed in disuse
models (6, 49), supporting the idea that disuse plays a role in
increased muscle weakness during exacerbation. Interestingly,
local inflammation determined by measuring interleukin
(IL)-6, IL-8, and tumor necrosis factor-␣ (TNF-␣) mRNA
revealed very low levels of IL-6 and IL-8 in the vastus lateralis
of these patients (16). TNF-␣ mRNA was not detectable (16).
These data suggest that local inflammation is likely not playing
a role in muscle weakness during exacerbation.
In a subsequent study, Crul et al. (17) established the gene
expression profile in the vastus lateralis muscle using microarray
analysis. This study showed that compared with patients with
stable COPD, several pathways leading to muscle atrophy and
mitochondrial dysfunction were activated in the muscles of patients during an acute exacerbation of COPD. In particular, the
ubiquitin-dependent protein catabolism, the Akt/FoxO pathway,
and apoptotic signaling were upregulated, whereas oxidoreductase
activity acting on NADP-NADPH, oxidative phosphorylation,
and the mitochondrial respiratory chain were downregulated (17).
Importantly, most of these pathways were already impaired in
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(Fig. 1) (16, 55, 74). The reduction in quadriceps force was not
due to the loss of body weight only because it still remained
when the analysis was limited to hospitalized patients with a
normal body mass index [BMI defined as the ratio of weight/
height2 (range,18.5–24.9 kg/m2) according to Worth Health
Organization classification; Ref. 84] (74). The reduction in
quadriceps force during hospitalization was significantly correlated with less improvement in walking time 1 mo after
discharge (55), showing that the loss of force during hospitalization had a serious and long-term consequence on functional
status. Importantly, quadriceps force partially recovered 3 mo
after discharge from hospital (Fig. 1) (74), indicating that
spontaneous functional recovery without any structured exercise program was slow. Obviously, any new exacerbation at
that time point would further affect muscle force and compromise functional recovery.
Interestingly, upper limb muscle function, which is usually
preserved in patients with COPD, is also affected during acute
exacerbations. Handgrip force was, indeed, reduced compared
with patients with clinically stable COPD (74). However, in
contrast to quadriceps strength, handgrip force did not further
decrease over time during hospitalization (74). But the deleterious effect of exacerbation is underlined by the reduction in
handgrip strength occurring more frequently and to a greater
extent in patients with a history of frequent exacerbation (4).
Finally, handgrip force dysfunction was associated with an
increased risk for hospital admission due to acute exacerbation,
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Gayan-Ramirez G et al.
EXACERBATION
Systemic inflammation
Dietary intake
Leptin
Corticosteroids
Hypoxia
Hypercapnia
Acidosis
Physical
inactivity
LIMB MUSCLES
Mitochondrial respiration
Anabolic factors
Muscle dysfunction
B
EXACERBATION
Systemic inflammation
Dietary intake
Leptin
Corticosteroids
Hypoxia
Hypercapnia
Acidosis
Mechanical
disadvantage
RESPIRATORY MUSCLES
Diaphragm injury
Muscle dysfunction
Fig. 2. Factors related to exacerbation that may affect limb (A) and respiratory (B) muscle function in COPD during acute exacerbations.
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Aspartate catabolism
Proteasomal degradation
Apoptosis
Oxidative stress
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patients with stable COPD and were further affected during
exacerbation. As in the previous study (16), the gene profiling
study did not find evidence of local inflammation in the muscle of
patients with COPD during an acute exacerbation (17). But this
study clearly highlighted the importance of proteolysis, apoptosis,
and mitochondrial dysfunction.
There are no data on alterations within other limb muscles
during an acute exacerbation. For the respiratory muscles, analysis
of postmortem diaphragm specimens from patients with severe
COPD revealed that acute-on-chronic ventilatory loading induced
extensive diaphragmatic injury and collagen accumulation (70).
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Gayan-Ramirez G et al.
studies have shown that administration of IL-6 to rats for 7
days resulted in respiratory and peripheral skeletal muscle
atrophy (39). Importantly, these data were obtained at IL-6
serum levels within the range attainable in patients (39). This
treatment was moreover associated with blood flow redistribution resulting from myocardial failure induced by IL-6 admin-
Stable COPD
A
Volume
TLC
POTENTIAL MECHANISMS LEADING TO MUSCLE WEAKNESS
DURING EXACERBATION
Fig. 3. Representative pressure-volume plots in stable COPD (A) and COPD
exacerbation (B). During exacerbation, worsening of expiratory flow limitation
results in dynamic hyperinflation with increased end expiratory lung volume
(EELV) and residual volume (RV) with a corresponding reduction in inspiratory capacity (IC) and inspiratory reserve volume (IRV), although total lung
capacity (TLC) is unchanged. As a consequence, tidal breathing is shifted
rightward on the pressure-volume curve, closer to TLC. Therefore, increased
pressures (⌬P) must be generated to maintain tidal volume (VT) During
exacerbation, intrapulmonary pressures do not return to zero at EELV. This
results in the development of an intrinsic positive end expiratory pressure
(PEEPi), which acts as an inspiratory threshold load (ITL) that the respiratory
muscles must first overcome to generate inspiratory flow. Reproduced from
(52) COPD exacerbations. 3: Pathophysiology, O’Donnell DE, Parker CM,
Thorax 61: 354 –361, 2006 with permission from BMJ Publishing Group Ltd.
IRV
IC
VT
EELV
∆P
RV
EELV
Pressure
COPD exacerbation
B
Volume
TLC
IRV
IC
VT
EELV
↑ ∆P
↑v ITL
RV
EELV
PEEPi
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Pressure
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The causes of muscle weakness during exacerbation (Fig. 2)
are probably multifactorial and may vary from patient to
patient. While most causes may affect both limb muscles and
respiratory muscles, some of them specifically target either the
respiratory muscles or the limb muscles. In fact, during exacerbations, additional systemic inflammation (15, 23, 74, 83),
oxidative stress (64, 65), impaired energy balance (15, 77),
alterations in the biochemical environment (hypercapnia, acidosis, hypoxia, depletion of metabolic substrates) (18, 32),
corticosteroid administration (20, 21), inactivity (55), and bed
rest may affect peripheral and respiratory muscles. But respiratory muscles are also subjected to the alterations occurring in
chest wall configuration caused by changes in lung volumes
during exacerbation (Fig. 3).
Enhanced systemic inflammation. Acute exacerbations are
associated with an additional increase in systemic inflammation
with higher blood levels of C-reactive protein (CRP), cytokines
(IL-6, IL-8, TNF-␣), leptin, endothelin-1, and fibrinogen (15, 23,
83). This acute systemic inflammation state during exacerbations
may potentially contribute to deterioration of muscle function and
probably affects both limb and respiratory muscles. In fact, systemic levels of IL-8 and IL-6 were shown to be inversely related
to isometric quadriceps strength (74). In that study, IL-8 was the
only systemic inflammatory marker to independently contribute to
the variance in quadriceps strength in hospitalized patients with acute
exacerbation of COPD (74). Systemic IL-8 was moreover inversely
correlated with handgrip force in these patients. This relationship was
specific to patients with acute exacerbation, as it was not observed in
patients with stable COPD (74). Finally, the presence of inflammatory markers within the muscle was not evident (16).
Whether increased cytokines may cause muscle weakness is
difficult to determine in human situations. However, animal
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body mass index, serum albumin) have been shown to be related
to hospitalization length and readmission (33).
Hypoxia, hypercapnia, acidosis. Acute exacerbations are
characterized by deterioration in pulmonary gas exchange
resulting in severe hypoxemia with or without hypercapnia
(18). Worsening of gas exchange is primarily due to increased
ventilation/perfusion mismatching and increased tissue oxygen
consumption (7). This acute hypoxemia status during exacerbation will add to muscle weakness and will affect the skeletal
muscles in several ways. Hypoxia alone can inhibit muscle
protein synthesis and may activate muscle proteolysis by stimulating the calcium-dependent proteases (37). Proteolysis via
the ubiquitin-proteasome pathway may be further activated
through additional acidosis that often accompanies hypoxemia
during severe exacerbations (37). Interestingly, acute exposure
to hypoxia in humans revealed that the protein levels of
hypoxia inducible factor-1␣, the master regulator of the cellular response to hypoxia, are only marginally altered in skeletal
muscles compared with other tissues (44), but the high preexisting level of hypoxia inducible factor-1␣ in skeletal muscle
may preclude any further important increase when environmental oxygenation is decreased during hypoxia (44). When
the hypoxia-inducible factor-1 pathway is activated it may
target several genes in muscles involved in glucose metabolism, angiogenesis, cell survival and apoptosis, oxidative metabolism, and even myosin heavy chain expression (44). Further, hypoxia may help generate low-grade systemic inflammation (42) that may alter skeletal muscle as discussed earlier.
Hypoxia also increased resting muscle oxidative DNA damage
in humans (45), which may also be deleterious for skeletal
muscles. Finally, acute hypoxia has been shown to accelerate
time to exhaustion of the adductor pollicis during voluntary
contraction (30). Hypoxia may also affect skeletal muscle by
indirect mechanisms that include loss of appetite, elevated
circulating levels of leptin, and reduced physical activity, all
being present in patients with COPD during exacerbation.
During severe exacerbations, respiratory pump failure due to
airflow obstruction and respiratory muscle weakness or fatigue
may lead to hypercapnic respiratory failure. Acute hypercapnic
acidosis can induce a negative influence on respiratory and
limb muscles. In humans, acute hypercapnic acidosis can
produce rapid and significant impairment of contractility of the
quadriceps and adductor pollicis muscles, in addition to increasing muscle fatigability (80). Also, diaphragm endurance
time was shown to be reduced in humans during hypercapnia
(40), but whether its contractility is altered remains controversial (40, 47). Quadriceps and intercostal muscles in patients
with COPD and acute respiratory failure showed lower intracellular muscle pH (29, 32, 40). Moreover, there was a close
relationship between arterial PCO2 and intracellular pH in these
patients just before intubation for mechanical ventilation (29,
40). Finally, in patients with COPD and acute respiratory
failure, the concentrations of ATP and creatine phosphate
measured on admission to an intensive care unit were low in
the intercostal muscles and particularly in the quadriceps muscle (32). These data indicate that the muscles were unlikely to
perform adequately, especially in view of the augmented work
of breathing. Dysfunction of the respiratory muscles to sustain
their task in the presence of low ATP and low creatine
phosphate may represent an important component of acute
respiratory failure in these patients.
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istration (39). By contrast, IL-8 administration to rats failed to
induce any effect on respiratory and peripheral muscles even at
high doses (100 and 250 ␮g·kg·day) (38). The effects of
TNF-␣ on skeletal muscle are divergent and have generated
doubt as to whether or not this cytokine has a role in muscle
dysfunction and wasting (5).
There are no data on relationship between systemic inflammation and respiratory muscle dysfunction during exacerbation.
Oxidative stress. During acute exacerbation, oxidative stress is
further increased in the vastus lateralis muscle of hospitalized
patients with COPD (17). Microarray analysis revealed upregulation of the transcripts of the response to oxygen species; more
specifically, the superoxide dismutase 2 and glutathione peroxidase 3 (17). Excessive reactive oxygen species production within
the muscle is known to target mainly mitochondria and myofilaments. This would lead to apoptosis, mitochondrial respiration
chain dysfunction, alteration in myofilament contractile properties, or a combination of these [reviewed in (14)]. In fact, gene
profiling in vastus lateralis muscle of hospitalized patients with
COPD showed that during acute exacerbation apoptosis is upregulated, whereas several genes involved in the mitochondrial
respiration chain process (e.g., cytochrome-c oxidase, a marker of
mitochondrial respiration) are downregulated (17).
Apoptosis normally leads to cell death but it can also cause
cell atrophy, especially in multinucleated cells (2) such as
skeletal muscle cells. In patients with heart failure, the magnitude of apoptosis in the vastus lateralis muscle was shown to
be associated with the degree of muscle atrophy (79), suggesting that apoptosis might play a role in determining muscle bulk
loss (79). As a result, enhanced apoptosis during exacerbation
may contribute to muscle wasting and may thus affect muscle
force. In addition, this may eventually postpone muscle recovery in these patients. Of note is that apoptosis during exacerbation of COPD may have been stimulated by excess reactive
oxygen species but also by reduced serum and muscle IGF-I
(16, 74). IGF-I is, indeed, known to exert antiapoptotic effects
(43). Therefore, its decrease during an acute exacerbation may
have contributed to enhanced apoptosis.
Downregulation of mitochondrial respiration chain processes
during acute exacerbation would add to the mitochondrial dysfunction already present in the muscle of patients with COPD
under stable situations (49, 60, 63). This will probably contribute
to further impair exercise capacity and may also slow down
functional recovery while decreasing fatigue resistance.
Whether oxidative stress is further enhanced in the respiratory muscles during exacerbation has not yet been determined.
Impaired energy balance. Impaired energy balance during
exacerbation may also play a role in muscle dysfunction. In fact,
dietary intake is reduced in patients with COPD during the first
days of an acute exacerbation because symptoms such as dyspnea
and fatigue make it difficult to eat more (77). Also, leptin, an
appetite-suppressing hormone and inflammatory cytokine, is increased during exacerbation (15) and, as such, it may further
contribute to reduced appetite. In addition, resting energy expenditure is acutely increased during the first days of hospitalization
(77). The low ratio between dietary intake and resting energy
expenditure was shown to be inversely related to elevated levels
of systemic inflammatory markers such as TNF-␣ receptor 55
(15). Importantly, prevalence of malnutrition is elevated in these
patients, and nutritional parameters (fat free mass, muscle mass,
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atrophy primarily affected lower limb muscles (48), and this
was not related to reduced physical activity because the latter
did not change in this model (46, 48). Taken together, these
data suggest that the limb muscles may be the preferential
target of emphysema and physical inactivity.
Physical inactivity negatively affects skeletal muscles. In
humans, the primary factor driving inactivity-induced locomotor muscle wasting is depressed protein synthesis (54), whereas
the effect of inactivity on proteolysis is less consistent (28, 34,
75). In fact, skeletal muscle inactivity is associated with oxidative stress that may directly stimulate proteolysis, depress
protein synthesis, and induce apoptosis [reviewed in (57)]. All
these processes are activated during exacerbations (17) and are
compatible with the presence of physical inactivity reported
under these circumstances. In addition, skeletal muscle inactivity leads to significant changes in mitochondrial morphology
and biochemical properties including decreased expression of
mitochondrial proteins, mitochondrial respiratory dysfunction,
and increased mitochondrial reactive oxygen species production [reviewed in (58)]. Worthwhile alterations in genes involved in mitochondrial function have been found in the vastus
lateralis muscle during exacerbation (17). These data are particularly important knowing that mitochondrial damage/dysfunction may contribute to inactivity-induced muscle wasting
[reviewed in (58)]. Physical inactivity has also been associated
with decreased IGF-I levels and alterations in the MyoD/
myogenin ratio (6, 49), which may further promote muscle
wasting, and both are reduced in the vastus lateralis muscle of
patients with COPD during acute exacerbation (16). Collectively, these data strongly support a role for physical inactivity
in impaired muscle function during exacerbation.
Mechanical disadvantage. Mechanical disadvantage concerns
the respiratory muscles only. During acute exacerbation, airway
resistance is abruptly increased, and this worsens expiratory flow
limitation. In addition, patients tend to adopt a rapid, shallowbreathing pattern that further limits the time available for lung
emptying but promotes greater dynamic hyperinflation. Worsening of expiratory flow limitation and exaggeration of dynamic
hyperinflation during exacerbation may contribute to functional
muscle weakness at least for the inspiratory muscles (52). Acute
dynamic hyperinflation further shortens the inspiratory muscles;
especially the diaphragm. Because the muscle is shorter during
contraction, it generates less force and, for the diaphragm, its
ability to generate pressure, in particular negative pleural pressure,
is impaired [reviewed in (19)]. Acute hyperinflation also affects
the parasternal intercostal and the external intercostal muscles, but
this effect is more related to rib orientation and motion than to the
ability of these muscles to generate pressure [reviewed in (19)].
Further, as a consequence of expiratory flow limitation, intrapulmonary pressures are positive at the end of expiration, representing intrinsic or autopositive end expiratory pressure (PEEPi) (52)
(Fig. 3). PEEPi acts as an inspiratory threshold load that the
respiratory muscles must overcome (52) (Fig. 3). This acute
inspiratory loading may intensify muscle injury and may take part
in decreased muscle strength, at least for the diaphragm (53, 70).
CONSEQUENCES OF EXACERBATIONS
Exacerbations have been associated with reduced exercise
capacity (13), further impairment of quality of life (71), and
increased likelihood of becoming housebound (26). Mortality
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Corticosteroid administration. Systemic corticosteroids are
part of the hospital management of COPD exacerbations. It is
well accepted that corticosteroids may affect respiratory and
peripheral muscle force (20 –22), and decline in fat free mass is
independently associated with the use of a maintenance dose of
oral corticosteroids (35). The mechanisms by which corticosteroids may affect muscle function are related to their ability
to compromise the production of contractile proteins through
inhibition of protein synthesis while downregulating the IGF-1
pathway and through activation of the ubiquitin proteasome
and lysosomal systems while notably upregulating myostatin
expression (a catabolic growth factor) (69).
During acute exacerbation, no relationship between the dose of
oral corticosteroids and the changes in quadriceps muscle force
between hospitalization day 3 and day 8 has been found (74). By
contrast, a negative correlation between corticosteroid intake and
changes in handgrip strength was reported during exacerbation
but this observation might have been confounded by disease
severity (68). There are no data on the effect of corticosteroids on
respiratory muscles during acute exacerbation.
Nonetheless, corticosteroids may have affected skeletal muscle
in several ways during acute exacerbation. Indeed, corticosteroids
are known to activate muscle proteolysis (24) and to indirectly
reduce protein synthesis through downregulation of IGF-I (24,
31). In fact, during exacerbation, proteolysis is enhanced in the
vastus lateralis muscle of hospitalized patients with COPD, while
IGF-I expression is repressed (16, 17). Corticosteroids are also
able to activate the mitochondrial-mediated apoptotic signaling
pathway in skeletal muscle (24), and this pathway is activated
during acute exacerbation. Further, corticosteroids exert an adverse effect on nitrogen balance and, in patients with acute
exacerbation of COPD, there is a negative correlation between
corticosteroid intake and nitrogen balance (68). Obviously, corticosteroids may take part in the development of skeletal muscle
weakness during an acute exacerbation of COPD.
Physical inactivity. During exacerbation, patients with COPD
limit their physical activity because of excessive dyspnea,
weakness, and tiredness. Quantitative measurement of physical
activity revealed that during acute exacerbation, patients with
COPD are very inactive (55). They spent less than 10 min per
day walking even when they are close to discharge (55). They
also remained inactive even 1 mo after discharge compared
with patients with stable COPD with similar disease severity
(55). This shows that physical inactivity is not simply the result
of bed rest during hospitalization. Moreover, patients with
frequent exacerbations of COPD recover their physical activity
level to a lesser extent than patients without frequent exacerbations (55). In fact, patients who did not improve their
walking distance within 1 mo after exacerbation are more
prone to be readmitted to hospital (55). Exacerbations are, in
addition, associated with a decline in outdoor activity for up to
5 wk after the onset of symptoms (26). Lower limb muscles are
particularly affected by physical inactivity, whereas respiratory
muscles are not. Indeed, the increased work of breathing
imposed by COPD and exacerbation dictates that respiratory
muscles overwork rather than decondition, like limb muscles
do (51). Importantly, reduced contractile activity is associated
with increased protein breakdown through activation of the
ubiquitin proteasome system (66) and decreased protein synthesis through inhibition of the Akt/TSC2/mTOR pathway
(27). Animal models also showed that emphysema-induced
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0
There are still strategies to be explored that may eventually
be combined with the interventions discussed above. First, the
beneficial effect of neuromuscular electrostimulation may be
sustained by implementing its home use. After a couple of
supervisory sessions, a patient may be able to apply it inde-
10
20
30
Time (Days after admission)
Fig. 4. Quadriceps force in patients with acute exacerbation of COPD admitted
to hospital and submitted to resistance training on day 2 of hospitalization for
7 days (solid circles, full line) and in control subjects (solid squares, dashed
line) receiving usual care and no training. Quadriceps force was assessed on
day 2 and day 8 of hospitalization, and at follow-up (1 mo after discharge).
Quadriceps force is expressed as a percent of the values obtained on day 2.
Values are mean ⫾ SEM. *P ⬍ 0.05 training vs. controls. Reprinted with
permission of the American Thoracic Society. Copyright © 2013 American
Thoracic Society. Troosters T, Probst VS, Crul T, Pitta F, Gayan-Ramirez G,
Decramer M, Gosselink R/2010/Resistance training prevents deterioration in
quadriceps muscle function during acute exacerbations of chronic obstructive
pulmonary disease/American Journal of Respiratory and Critical Care Medicine/181/1072–1077. Official journal of the American Thoracic Society.
pendently (11) and the benefit may be ensured with regular
feedback to the hospital and training modalities adapted in
consequence. In addition, pharmacological support with an
antioxidant or antiprotease may help maintain muscle bulk, and
this might eventually be combined with muscle training. Otherwise, supplementation with essential amino acids to increase
fat free mass or with polyunsaturated fatty acids, which have
been shown to improve exercise tolerance, should be considered. Also, simple but proven to improve functional exercise
capacity, the use of wheeled walking aids such as the rollator,
may help and motivate a patient to be physically active (59).
CONCLUSION
In conclusion, it is now well recognized that acute exacerbations in addition to causing deterioration of lung function are
particularly deleterious for skeletal muscles. Exacerbations rapidly induce loss of muscle force and activate different pathways
leading to muscle wasting and dysfunction. Because functional
recovery after an exacerbation is long and partial, the adverse
effects of exacerbations may accumulate especially in patients
with frequent exacerbations of COPD. Therefore, a need exists for
action plans, and available data indicate that it is possible to limit
the impact of exacerbations on skeletal muscles. Resistance training or neuromuscular electrostimulation either applied during
hospitalization or immediately after exacerbation represent encouraging options because they can improve muscle strength,
facilitate functional recovery, or both. Neuromuscular electrostimulation is even applicable and beneficial for patients who need
mechanical ventilation. Importantly, pulmonary rehabilitation
consisting of exercise training was proven to reduce hospital
admissions and mortality, and this effect should not be neglected.
J Appl Physiol • doi:10.1152/japplphysiol.00847.2012 • www.jappl.org
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STRATEGIES TO BE EXPLORED
*
*
INTERVENTIONS
Knowing the impact of exacerbation on skeletal muscle,
several interventions based on rehabilitation have been used
early or late after exacerbation to minimize the consequences
of exacerbation on muscle. A Cochrane Collaboration metaanalysis showed that pulmonary rehabilitation immediately
after an exacerbation significantly improved exercise capacity
and reduced hospital admissions and mortality (61). Pulmonary
rehabilitation after exacerbation was also associated with an
improvement in quadriceps strength (50, 72). A significant
improvement in quadriceps force and 6-min walking distance
were reported after a 6-wk neuromuscular electrostimulation
program initiated during admission to an intensive care unit for
acute COPD exacerbation (1). This was also associated with a
decrease in muscle oxidative stress, improvement in myosin
heavy chain content, and increased type I fiber proportion (1).
Interestingly, in bed-bound patients with COPD receiving
mechanical ventilation, neuromuscular electrostimulation may
show improved muscle function and decreased number of days
needed to transfer from bed to chair (85).
So far, very few interventions have taken place during the
hospitalization period. Resistance training started from the second
day of hospitalization was able to increase quadriceps force by
10% and resulted in an improvement of the 6-min walking
distance at discharge (Fig. 4) (76). In addition, anabolic markers in
the muscle were increased (76), whereas 1 mo after discharge, the
functional status and muscle force remained better in the group
that followed training during the exacerbation (Fig. 4) (76),
suggesting that this modality may facilitate functional recovery
after an acute exacerbation. On the other hand, nutritional intervention during hospitalization with protein intake exceeding 1.5
g/kg body wt was shown to result in protein and total energy
intake improvement, but this did not translate into improvement in
muscle strength (68, 78). The strong correlation between the
degree of muscle wasting and the dose of corticosteroids in these
nutritionally depleted patients with COPD suggests that prevention of muscle wasting is likely to be more difficult in patients
treated with a corticosteroid (68).
1297
Gayan-Ramirez G et al.
120
QF (% day 2)
increases with the frequency of exacerbations, especially if
hospital admission is required (73). In fact, patients with
COPD and recurrent hospitalization and high medical consumption are characterized by skeletal muscle weakness rather
than impaired pulmonary function (21). Further, acute exacerbation of COPD is associated with an increase in both prevalence and severity of generalized muscle dysfunction measured
by handgrip strength, and maximal inspiratory and expiratory
pressure (81). Importantly, both prevalence and severity remain elevated even while recovering clinical stability (81). Of
note, skeletal muscle force recovery after acute exacerbation is
slow and partial (74). Thus any new exacerbation before
complete force recovery may particularly be detrimental for
patients with COPD and frequent exacerbations.
•
Review
1298
Striated Muscle Weakness and Exacerbation
Obviously, it is important to actively slow down the impact of
exacerbations on skeletal muscle. Several treatment options were
shown to be effective, and their systematic use in COPD exacerbations should be promoted.
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