Respiratory Diseases and Muscle Dysfunction: Review

Review
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Respiratory diseases and

muscle dysfunction
Expert Rev. Respir. Med. 6(1), 75–90 (2012)
Joaquim Gea*, Many respiratory diseases lead to impaired function of skeletal muscles, influencing quality of
Carme Casadevall, life and patient survival. Dysfunction of both respiratory and limb muscles in chronic obstructive
Sergi Pascual, pulmonary disease has been studied in depth, and seems to be caused by the complex interaction
of general (inflammation, impaired gas exchange, malnutrition, comorbidity, drugs) and local
Mauricio Orozco-Levi
factors (changes in respiratory mechanics and muscle activity, and molecular events). Some of
and Esther Barreiro these factors are also present in cystic fibrosis and asthma. In obstructive sleep apnea syndrome,
Servei de Pneumologia, Hospital del repeated exposure to hypoxia and the absence of reparative rest are believed to be the main
Mar – IMIM, Departament de Ciències
causes of muscle dysfunction. Deconditioning appears to be crucial for the functional impairment
Experimentals i de la Salut (CEXS),
Universitat Pompeu Fabra, CIBER de observed in scoliosis. Finally, cachexia seems to be the main mechanism of muscle dysfunction
Enfermedades Respiratorias (CIBERES) in advanced lung cancer. A multidimensional therapeutic approach is recommended, including
ISC III, Barcelona, Catalunya, Spain pulmonary rehabilitation, an adequate level of physical activity, ventilatory support and nutritional
*Author for correspondence:
Tel.: +34 93 248 3138
interventions.
Fax: +34 93 248 3425
[email protected] Keywords : drugs • exercise limitation – muscle remodeling • hypoventilation • inflammation • limb muscles
• muscle dysfunction • respiratory diseases • respiratory muscles
Any impairment in striated muscle function internal intercostals and those constituting the
can interfere with the performance of daily abdominal wall. Skeletal muscles located in the
activities, particularly for a patient already liv- limbs (and also called peripheral muscles), are
ing with a respiratory disorder. However, the involved in the movements of the body. Any
interaction between the respiratory and mus- impairment in their function can interfere with
culoskeletal systems is not always considered the performance of daily activities.
in the clinical management of these patients. Muscle function becomes impaired in many
Striated muscles are contractile elements that different respiratory disorders, such as chronic
provide organisms with physiological func- obstructive pulmonary disease (COPD), cystic
tions, such as movement and generation of fibrosis, bronchial asthma, obstructive sleep
both air- and blood-flow. The latter two func- apnea syndrome (OSAS), kyphoscoliosis and
tions are essential for respiratory gas exchange. lung cancer. Although changes in respiratory
The generation of airflow requires the action of mechanics in these diseases primarily target
inspiratory muscles. When this muscle group respiratory muscles, limb muscles can also
contracts, the changes in intrathoracic pres- be affected. In addition, respiratory and limb
sure allow air to enter the lungs. When these muscle dysfunction can occur in patients with
muscles relax, the air exits from the respira- myopathies, neurological and neuromuscular
tory system. If additional effort is required to junction disorders, chronic heart failure, sepsis
exhale, the expiratory muscle group contracts, and other critical illness. In the intensive care
increasing the alveolar–atmosphere pressure unit (ICU), the condition called ICU muscle
gradient. Although the diaphragm is the main weakness is not only a limb problem but can also
inspiratory muscle, specifically in young and hamper weaning from mechanical ventilation.
healthy subjects when they are at rest, other This review aims to briefly present basic
muscles progressively participate in the effort concepts of skeletal muscle physiology and to
as ventilatory demands increase. These include describe in-depth the muscle function impair-
external intercostals, parasternal and, to a ment occurring in some of the most prevalent
lesser degree, the scalenes, sternocleidomas- respiratory conditions, defining the factors and
toid, latissimus dorsi, serratus and pectoralis mechanisms involved in the etiopathogenesis of
muscles. The main expiratory muscles are the muscle dysfunction in this setting.
www.expert-reviews.com 10.1586/ERS.11.81 © 2012 Expert Reviews Ltd ISSN 1747-6348 75

Review Gea, Casadevall, Pascual, Orozco-Levi & Barreiro
Muscle physiology Disuse of respiratory muscles only occurs under very specific con-
The two main functional properties of both respiratory and limb ditions, such as mechanical ventilation. Conversely, overloading
muscles are: strength and endurance. The former can be defined occurs more frequently because many different situations result in
as the ability to develop a brief maximal effort, whereas the lat- increased breathing. On the one hand, airway resistances increase
ter could be described as the ability to maintain a submaximal in obstructive diseases. On the other, pulmonary hyperinflation
contraction over time. Strength mainly depends on muscle mass, or changes in thorax geometry can deny respiratory muscles their
although other factors also contribute, such as muscle length, optimal length for contraction. Although some studies support
innervation, fiber size and the proportion of predominantly that these factors are essential for respiratory muscle dysfunction,
anaerobic fibers. Endurance is related to the aerobic properties of additional elements cannot be excluded.
the muscle, which in turn, are conditioned by capillary density,
proportion of type I fibers and enzyme activity in the oxida- Peripheral muscles
tive pathways, among other factors. When the strength and/or The striated muscles of the upper and lower limbs constitute
endurance of skeletal muscles is reduced, this is called muscle the peripheral muscles; the concept can also include the muscles
dysfunction and can be characterized in two ways: weakness and of the shoulder and pelvic girdles. The muscles of the upper
fatigue. Muscle weakness is related to the loss of muscle strength. limbs are essential for manipulating objects, and for many of
Therefore, it can be identified easily in clinical conditions through the tasks involved in personal care. In addition, some of them
the assessment of muscle force (determination of pressures gener- can be recruited to serve as ventilatory muscles when these are
ated by respiratory muscles and standard dynamometry to assess overburdened by respiratory loads [7,8] . In turn, the muscles of
limb muscles). Weakness is a constitutive and relatively stable the lower limbs are essential for locomotion and exercise, and
situation, and the muscle requires long-term therapeutic meas- are crucial for many daily activities. The clinical implications
ures (training and nutritional interventions). By contrast, muscle of peripheral muscle dysfunction are important, as patients may
fatigue is a temporary dysfunction related to endurance, and is be unable to work or take care of themselves, become extremely
primarily resolved by rest. It can be identified by neurophysi- dependent on those around them and experience a reduction
ological (changes in the high/low frequencies ratio or in centroid in their quality of life. Since tests for the functional proper-
frequency) or mechanical (transient inability to perform a target ties of peripheral muscles are relatively simple [9] , we know that
task) indicators. Both conditions, weakness and fatigue, can be many disorders can induce (or are associated with) limb muscle
present simultaneously in the same patient, as a weak muscle will dysfunction, including COPD, scoliosis, chronic heart failure
become fatigued much more easily. and cancer cachexia, among others. Peripheral muscles are very
sensitive to disuse (deconditioning) and nutritional abnormali-
Respiratory muscles ties, two factors that many authors believe are pivotal for the
Inspiratory muscles ensure an appropriate level of ventilation occurrence of muscle dysfunction. However, other factors can
to facilitate pulmonary gas exchange. Therefore, their dysfunc- also be implicated.
tion will result in hypoxemia and hypercapnia, and in venti- Peripheral muscles are readily accessible for tissue sampling,
lated patients can lead to difficulties in the weaning process. facilitating analysis of the cellular and molecular changes that
Malfunction of expiratory muscles will, in turn, give rise to dif- are associated with muscle dysfunction. In the following sections,
ficulties upon exertion, coughing and attempts to expectorate these changes and their possible mechanisms will be reviewed.
secretions from the airways. Functional assessment of respiratory However, it is important to clarify that many of these structural
muscles is slightly more complicated than that of limb muscles, and molecular studies have been performed in samples from the
but can be achieved through determination of respiratory pres- quadriceps muscle, particularly its external part (vastus latera-
sures. A large number of studies have demonstrated that respi- lis). It is possible to speculate that not all the findings should be
ratory muscle function can also be impaired in widely diverse directly extrapolated to other peripheral muscles, whose functions
disorders. These include COPD, cystic fibrosis, chronic asthma, are essentially different from those of the anterior thigh. Some
scoliosis, neuromuscular diseases and also ICU muscle weakness studies performed in the upper limb muscles appear to confirm
and sepsis. this hypothesis [10,11] .
Molecular and cellular events occurring in respiratory muscles Muscle dysfunction can occur not only as a consequence of
with an impaired function are identified through biopsy analysis. a disease or a treatment, but also in some more physiological
However, the sampling of these muscles is always very invasive, circumstances, such as aging and extreme sedentary lifestyle.
and therefore their structural and molecular properties are studied As mentioned above, it has been well described in COPD, bron-
less frequently than in limb muscles. Most studies have been per- chial asthma and lung cancer cachexia, among others. It is also
formed in the diaphragm, with samples obtained during thoracic characteristic of other disorders targeting the respiratory system,
or abdominal surgery owing to associated diseases [1–4] . However, such as OSAS, neuromuscular and rib cage abnormalities [12–15] .
data are also available regarding other inspiratory muscles, such The following sections review the causes and mechanisms of
as external intercostals, parasternals or even accessory muscles, muscle dysfunction in the most common disorders that target
such as latissimus dorsi [5] . Regarding expiratory muscles, data are the respiratory system and also respiratory and/or peripheral
scarce, but there are some reports on the major oblique muscle [6] . muscles (Box 1) .
76 Expert Rev. Respir. Med. 6(1), (2012)

Respiratory diseases & muscle dysfunction Review
Respiratory disorders
Box 1. Respiratory system and muscle dysfunction.
Chronic obstructive pulmonary
disease Respiratory disorders, frequent comorbidities and drugs known to alter muscle
COPD is a highly prevalent condition structure and/or function are listed.
characterized by nonreversible airf low Respiratory disorders:
obstruction [301] . The main cause of • Chronic obstructive pulmonary disease
COPD is tobacco smoking, which results • Bronchial asthma
in inflammatory phenomena leading to • Sleep apnea–hypopnea and related syndromes
destruction of lung parenchyma and air- • Cystic fibrosis
way remodeling. In addition to airway • Scoliosis and other thoracic deformities
obstruction, COPD results in pulmonary • Idiopathic pulmonary hypertension
hyperinflation, increased airway resistance, Other conditions:
changes in pulmonary compliance and gas • ICU muscle weakness – deleterious effects of mechanical ventilation
exchange abnormalities, characterized by • Lung cancer (cachexia)
hypoxemia and, in some cases, hypercap- Frequent comorbidities:
nia. As a result, patients experience ventila- • Chronic heart failure
tory limitations that impair their exercise • Sepsis
tolerance. However, COPD is a heteroge- • Diabetes mellitus
neous disease and patients may also show • Aging – sarcopenia
extrapulmonary involvement, including
Drugs:
malnutrition, and abnormalities in skel-
• Corticosteroids
etal muscles, blood cells, renal and nerv-
• Antagonists of b-adrenergic receptors
ous systems and even bone metabolism
• Statins
[16–19] . Muscle dysfunction is probably the
best-studied extrapulmonary manifestation • Diuretic drugs
occurring in COPD. It includes abnormali- • Phosphodiesterase 5 inhibitors
ties in the strength and endurance of both ICU: Intensive care unit.
respiratory and limb muscles [3,20] , and is believed to be of mul- including inflammation, oxidative stress, nutritional abnormali-
tifactorial origin, with local and general factors interacting to ties and the effects of tobacco and some drugs (Figure 1) [27–30] . The
modify the phenotype and function of any particular muscle. combination of these systemic factors and the adaptive changes
Muscle dysfunction is relevant because it reduces exercise capac- that occur in the face of increased mechanical loads leads to
ity, which ultimately affects quality of life and influences patient important changes in the phenotype of respiratory muscles. On
survival [21] . the one hand, the percentages of myosin heavy chain I, type I
Respiratory muscle dysfunction is frequently observed in many fibers (with a predominantly aerobic metabolism), capillary and
COPD patients [22–24] , mostly in those with more advanced stages mitochondria increase in the diaphragm, leading to a more oxida-
of the disease, and can involve both inspiratory and expiratory tive phenotype [1–3,31,32] . On the other hand, sarcomerae appear
muscle groups. Regarding inspiratory muscle dysfunction, it is to shorten in this muscle, partially restoring their optimal length
believed to mainly be the consequence of changes in lung function for contraction [2] . Interestingly, these positive phenomena coex-
[23,25] . On the one hand, pulmonary hyperinflation, present in ist with signs of myopathy (paracristalline inclusions), as well as
many patients, has a dramatic impact in the length–tension rela- oxidative stress, changes in the expression of local cytokines and
tionships of both the diaphragm and intercostal muscles (Figure 1) protein imbalance [33–35] , all of which can contribute to the loss of
[7]. These muscles become shorter and larger, respectively, than muscle function. Data from external intercostal, parasternal and
their optimal length for generating force [25] . In addition, the cos- accessory muscles are much more scarce, but also suggest a com-
tal and crural parts of the diaphragm lose their summatory action bination of adaptive and negative phenomena [5,36–39] . Regarding
and become physiologically independent [26] . On the other hand, expiratory muscles, the information is even more scant. Although
increased airway resistance and impaired gas exchange lead to an their function deteriorates in many COPD patients [24,40] , some
imbalance between demand and supply in the muscle [7,8] . One of of the factors should be different from those acting in the inspira-
the reasons to believe that hyperinflation is crucial for the develop- tory or peripheral muscle groups. Changes in lung volumes will
ment of respiratory muscle dysfunction in COPD is that although only negatively affect the length–tension relationships of inter-
these patients develop lower respiratory pressures than healthy nal intercostals, not those of abdominal muscles [41] . Moreover,
subjects, they can generate even greater force than the controls deconditioning is unlikely since expiratory muscles are chronically
when both groups perform a test maneuver at similar high lung activated for both the breathing effort and coughing in COPD
volumes [23] . This finding also suggests some muscle adaptation patients [42,43] . However, they are also subject to all of the systemic
to pulmonary hyperinflation. However, respiratory muscles are factors present in other muscles. All of these circumstances result
subjected to the same deleterious general factors as other muscles, in changes to their phenotype and metabolism [7,8] . In this regard,
www.expert-reviews.com 77
contribute to reduce both the strength and

resistance of lower limb muscles in COPD
Airway resistance
patients. Moreover, some studies support
Tobacco increased
Dynamic compression the idea of impaired bioenergetics in the
of the airways quadriceps of such patients, showing that
Ribcage muscle this muscle is inefficient in its intracellular
dysfunction Changes in ribcage use of oxygen [47,48] . Therefore, it could
compliance
require greater oxygen consumption than
Changes in healthy subjects for the same amount of
Pulmonary lung compliance Secondary pulmonary
hyperinflation hypertension
work. The quadriceps also show major oxi-
VA
dative stress that targets essential proteins
in muscle structure and metabolism [59,60] .
VA/Q inequality Q Heart
Drugs, As a result, muscle damage occurs [61] , and
dysfunction
systemic inflammation
and oxidative stress
there is some evidence that this phenom-
Metabolic mismatching enon is associated with defects in the mus-
(nutrients, oxygen) Diaphragmatic cle regeneration process [62] . The latter, in
dysfunction Exacerbations
VO2 O 2D
turn, might be related to the underexpres-
Flattened and
sion of some local cytokines [63] , but more
Abdominal wall
muscle dysfunction shortened diaphragm evidence is necessary. Other authors have
reported increased levels of inflammatory
cells and proinflammatory cytokines in the
Expert Rev. Respir. Med. © Future Science Group (2012)
quadriceps muscle of COPD patients [64] .
Figure 1. Contributing factors to the respiratory muscle dysfunction of chronic All of these phenomena could contribute
obstructive pulmonary disease patients. to the loss in muscle mass and function
O2D: Oxygen delivery; Q: Perfusion; VA: Alveolar ventilation; VO2: Oxygen consumption. in the lower limbs. By contrast, muscles
located in the scapular girdle and upper
some reports have described fiber atrophy and minor changes in limbs show fewer dramatic changes [10,31,65] , contributing to the
the proportions of fiber types in expiratory muscles of COPD heterogeneity of muscle adaptations that characterizes COPD.
patients [6,8] . Therefore, we can conclude that adaptation is not This is not surprising because these muscles probably have a
homogeneous for all respiratory muscles. lower exposure to a reduction in their activity. Moreover, they
As discussed above, peripheral muscles constitute a heterogene- can even show an increase in their activity, as they frequently
ous group involved in many different tasks. The function of both support ventilation under increased loads in COPD patients. For
lower and upper limb muscles appears to be impaired, to vary- instance, normal, hypertrophic and atrophic fibers coexist in the
ing degrees, in many COPD patients [9,24,44–48] , contributing to deltoid muscle, which preserves its fiber type proportions and
their exercise limitations [46,47,49,50] . The main cause of peripheral oxidative enzyme activities in COPD patients [10,11] . In a similar
muscle dysfunction appears to be deconditioning due to a reduc- way, brachial biceps show fiber atrophy but maintain their fiber
tion in daily activities (Figure 2) [51,52] . This reduction would be the type percentages [65] .
product of both the initial ventilatory defect and the emotional Acute exacerbations contribute to the progression of COPD and
impairment frequently associated with COPD. A strong argu- the deterioration of muscle function [66] . The increased inflamma-
ment in favor of the key role played by muscle deconditioning tory load present in the lung during exacerbations may also have
in peripheral muscle dysfunction is that most of the changes systemic repercussions and affect other regions, including skeletal
described can be reversed by muscle training [51,53] . However, muscles. In this regard, some authors have reported a reduction in
some of the changes are irreversible [47,51] , which suggests that muscle mass in various parts of the body during exacerbations [67] .
other factors may be implicated. Among these are the general This would be the result of a negative protein balance [68] and the
factors described as affecting the respiratory muscles, which also activation of multiple pathways leading to a reduction in MyoD
affect limb muscles: systemic inflammation and oxidative stress, and IGF-1, and subsequent muscle atrophy [69–72] . In addition,
tobacco smoking, nutritional abnormalities, comorbidity and the reduction in activity that frequently occurs during an exac-
drugs, among others (Figure 2) [20] . The many studies of structural erbation would also negatively affect limb muscles. In the case of
and molecular changes in the quadriceps of COPD patients have respiratory muscles, the situation would be further aggravated by
established that this muscle undergoes protein imbalance and the indirect effects of the exacerbation in the mechanical loads of
atrophy (see next sections), as well as losses in different aerobic the ventilatory system. Conversely, muscle dysfunction has been
components. These include declines in myosin heavy chain I shown to be an independent risk factor for severe exacerbations
expression, percentage of type I fibers, fiber size, capillary density requiring hospital admission [73] .
and myoglobin content, as well as impaired enzyme activities in As a general conclusion, muscle dysfunction associated with
the oxidative pathways [53–58] . All of these components could COPD can involve many muscle groups. The extension and

intensity of the functional impairment is

a consequence of the complex interaction Tobacco
of local and general factors in each muscle.
Deconditioning†
Bronchial asthma
This disorder is characterized by reversible Exacerbations
episodes of airflow obstruction, which are
the consequence of airway inflammation Upper limb muscle dysfunction
and edema, as well as hyperresponsiveness
of bronchial smooth muscles [302] . Limb Drugs
muscle weakness can occur, but is almost
exclusive to chronic patients, as it is related Systemic inflammation
to steroid treatment [74] and muscle disuse Systemic oxidative stress
[75] . Unfortunately, structural and meta- Reduced nutrients
bolic analyses of these muscles are surpris- and oxygen delivery
ingly scarce, and the potential bias of a ster- Lower limb muscle dysfunction
oid myopathy (see ‘Treatments commonly
used in respiratory disease patients’ sec- Deconditioning
tion) is not always controlled. From some
of these studies we know that magnesium Local inflammation
tends to be diminished in the quadriceps and oxidative stress
muscle of these patients [76] . However, the COPD myopathy‡
precise impact of this abnormality on mus-
cle function remains unknown. Respiratory Expert Rev. Respir. Med. © Future Science Group (2012)
muscles in turn appear to maintain or Figure 2. Contributing factors to the peripheral muscle dysfunction of chronic
improve their functional properties in obstructive pulmonary disease patients.
chronic asthma patients, even in the pres- †
Deconditioning is clearly involved in lower limb muscle dysfunction but not so much for
ence of pulmonary hyperinflation [77–80] . upper limb muscle dysfunction.
‡
The existence of a true COPD myopathy is also controversial.
Since these muscles are actively recruited in
COPD: Chronic obstructive pulmonary disease.
chronic asthma, it is possible to hypothesize
a training-like phenomenon similar to that present in COPD. patients can show impaired strength and endurance in both
As for peripheral muscles, there are few studies on the structural inspiratory and limb muscles, although fatigability appears to
and molecular properties of respiratory muscles in patients with only be increased in the inspiratory group [88] . These abnormali-
asthma. Moreover, most research has been carried out on necropsy ties appear to be related to the absence of reparative rest during
specimens. Some studies suggest that the diaphragm is hyper- sleep deprivation, and mostly to the presence of hypoxia–nor-
trophied in patients with chronic asthma [80] , but others have moxia cycles [8,89] . Functional impairment is associated with cel-
reported fiber atrophy [74] . It is possible that the relative weight lular and molecular changes in different limb muscles (quadri-
of the contributing factors in different populations of chronic ceps and tibialis anterior), such as increases in the size of type II
asthma patients may account for these conflicting results. fibers, protein content and the number of blood vessels [90,91] .
Acute asthma attacks represent a completely different situation. The increase in capillarity in turn is probably the result of the
In this case, the combination of an acute increase in mechanical overexpression of VEGF [92] , as a consequence of the repeated
loads (greater airway resistance and pulmonary hyperinflation) bouts of hypoxia. Sleep deprivation and hypoxia would also affect
[81] , and deteriorated oxygen delivery to the tissues act on a nonrespiratory muscles [93] , but in this case another factor is present:
trained muscle and can result in transitory muscle dysfunction inspiratory muscles perform progressively submaximal efforts in
[82] . However, if the situation progresses to a severe asthma exacer apneic events [94,95] that could result in muscle fatigue, but might
bation, rhabdomyolysis and/or muscle fatigue may occur [83,84] , also mimic muscle training. In fact, respiratory muscle strength
and it may even be fatal. and endurance appear to be roughly maintained in many patients
with sleep apnea [88,96–98] . However, as previously mentioned,
Respiratory disorders related to sleep there is a reduction in their reserve against fatigue [96,97] , mostly
Sleep apnea syndrome and related disorders are characterized in those patients with severe disease. Structural and molecular
by the presence of repeated total or partial occlusions of the studies performed in the external intercostal muscle have dem-
upper airways during sleep. The consequences include noctur- onstrated an increase in the size of type II fibers coexisting with
nal hypoxemia, loss of sleep structure and diurnal hypersomnia a decrease in oxidative stress and the proportion of type I fibers
[85–87] . Skeletal muscle dysfunction has been described in patients [99] . Although treatment with continuous positive airway pressure
with sleep disorders, and specifically in those with OSAS. These (CPAP) restores sleep quality and reduces nocturnal ventilatory
effort, it only partially improves respiratory muscle function [97,99] . associated with structural and molecular changes, including mus-
The lack of complete restoration might be explained by the per- cle atrophy and a reduction in the proportion of aerobic fibers in
sistence of oxidative stress in the muscle [99] and the probable the quadriceps muscle [111] .
presence of pulmonary hyperinflation due to the CPAP treatment.
Finally, upper airway muscles, which have an important role in Other circumstances related to respiratory system
the pathophysiology of OSAS, have shown mechanical, structural targeting of skeletal muscles
and metabolic changes in patients suffering from this condition. ICU muscle weakness
Musculus uvulae, for instance, shows an increased strength along Many different factors, such as systemic inflammation, sepsis,
with larger fibers, a higher protein content and better anaerobic multiorganic failure, malnutrition, malposition, drugs, dyselec-
enzyme capacity in OSAS patients than in nonapneic snorers trolytemia and mechanical ventilation [112–115] , can contribute
[100,101] . Although genioglossus dysfunction has been reported in to muscle weakness in critically ill patients. These and other
patients with OSAS, cellular findings are less impressive [102] and still unknown factors can result in axonal and demyelinating
only a mild increase in the proportion of anaerobic fibers has been neuropathies, defects in the neuromuscular junction and acute
reported [103] . Interestingly, CPAP reverse these functional and myopathies. The latter have specific characteristics, including
structural changes, suggesting that these are the consequence, fiber atrophy, the loss of myosin and the presence of mitochon-
and not the cause, of the obstructive problem. dria with paracrystalline inclusions [116,117] . The consequences
of muscle dysfunction in ICU patients are very relevant because
Cystic fibrosis the weaning process will be more difficult as a result [118,119] ,
Muscle dysfunction is also frequent in cystic fibrosis. Cachexia, and intense rehabilitation is required to ensure reintegration into
systemic inflammation and gas exchange abnormalities are fre- everyday activities.
quently associated with advanced stages of the disease, potentially The different modalities of mechanical ventilation (MV) assist
targeting all skeletal muscles [104,105] . These factors, along with or substitute for respiratory muscles in their function of providing
deconditioning, will determine the weakness reported for limb ventilation to maintain pulmonary gas exchange. Classical MV
muscles. However, respiratory muscles will face a chronic increase with anesthesia-paralysis results in early respiratory and peripheral
in ventilatory workloads, which would have effects similar to muscle dysfunction. This appears to mainly be the consequence
those reported in COPD patients. Therefore, although structural of inactivity, a very harmful factor that can induce diaphragm
studies are lacking, this muscle group would exhibit phenotypes atrophy at only 48 h of MV [113] . By contrast, noninvasive MV
and function resulting from the complex interaction of multiple and those forms of classical MV involving the periodic use of
deleterious factors with a training effect [105] . respiratory muscles do not appear to induce severe dysfunction
because contractile activity is preserved. On the contrary, in most
Scoliosis & other thoracic deformities cases they provide rest to fatigued muscles and reduce the work
Scoliosis is defined by a lateral curvature of the spine associated of weakened muscles.
with vertebral rotation. This also results in chest deformity, back
pain, ventilatory restriction, respiratory and limb muscle weakness Lung cancer cachexia
and exercise limitation [15,106] . Although respiratory muscle dys- Cachexia is a complex metabolic syndrome characterized by the
function has classically been attributed to chest deformity, limb loss of muscle mass, which is common in advanced malignant
muscle dysfunction appears to be the consequence of decondition- diseases, including lung cancer. Anorexia is frequently associ-
ing, probably thorough the development of local oxidative stress ated with cachexia [120,121] , which targets muscle by inducing
[106] . Therefore, especially in adolescents with scoliosis, muscle protein imbalance and atrophy [122] , both resulting in muscle
training would improve their physical performance. By contrast, weakness. On the one hand, gluconeogenesis degrades structural
chest surgery options do not appear to improve muscle function and functional muscle proteins as a source of energy. On the
in these patients [Gea J et al., Unpublished Data] . In individuals with other, protein synthesis also becomes affected [123–125] . Moreover,
advanced stages of thoracic deformity and chronic respiratory fail- some cytokines, such as TNF-a, IL-1b, IL-6 and IFN-g [126,127] ,
ure, noninvasive mechanical ventilation can be useful to improve oxidative stress derived from metabolic changes and the use of
ventilation and gas exchange [107,108] . antineoplastic drugs appear to be directly involved in this pro-
tein imbalance [128,129] . Peripheral muscle weakness occurring in
Idiopathic pulmonary hypertension cachectic patients causes their quality of life to deteriorate through
This condition is characterized by an increase in the blood pres- progressive limitation of their daily activities. In addition, ventila-
sure in pulmonary vessels. One of the most frequent symptoms tory failure may occur when respiratory muscles become affected.
in idiopathic pulmonary hypertension is exercise intolerance. In fact, a third of deaths in cancer patients have been attributed
Although this is believed to be caused mainly by vascular fac- to muscle dysfunction.
tors, some authors have suggested a role for muscle dysfunction Skeletal muscle wasting is a prominent feature in patients with
[109,110] . This would affect both respiratory and peripheral mus- lung cancer [130] , even in those with normal bodyweight [131] .
cles, suggesting the involvement of systemic factors. Moreover, In addition, this has been shown to be not only a risk factor for
the impairment in functional outcomes has been shown to be prognosis, but a predictor of cancer treatment toxicity [131] . In the

same regard, proteolysis has been shown to be negatively related of proinflammatory cytokines [150] . Oxidative stress is the result
to survival in non-small-cell lung cancer [132] . of an imbalance between reactive oxygen species, a product of
aerobic metabolism, and antioxidant mechanisms present in cells
General factors involved in muscle dysfunction in and tissues. When the action of oxidants overcomes that of anti-
respiratory disorders oxidants, certain molecules become modified and their function
Although some general factors, such as tobacco smoking, are more is impaired as a result. Oxidative stress has been found in various
specific to COPD, others (systemic inflammation, sedentarism, organs of COPD patients, including the lungs, blood and mus-
comorbidity, aging, drug effects and so on) are common to vari- cles [4,34,59,151] . Although both respiratory and peripheral muscles
ous respiratory diseases. Below, we review the most relevant gen- exhibit oxidative stress, it appears to be greater in the limbs of both
eral factors believed to influence muscle function in respiratory these patients and animal models of COPD [4,60,152] .
patients:
Nutritional abnormalities
Tobacco smoking Although relatively frequent in COPD, cystic fibrosis, scoliosis
Different reports appear to indicate that tobacco smoking per se and lung cancer [104,105,130,153,154] , nutritional impairment is rela-
can induce muscle dysfunction by different mechanisms, includ- tively rare in other conditions, such as bronchial asthma. In the
ing oxidative stress and a decrease in protein synthesis [30,133–135] . particular case of COPD there is wide geographical diversity in
Therefore, a point that still remains unclear is whether the initial the prevalence of nutritional abnormalities. The range is from
stimulus that affects the muscle is just the direct result of the approximately 5% in Mediterranean countries to 25% or more
aggressive action of smoking itself or is secondary to the inflam- in Northern Europe and North America [155] . Nutritional abnor-
mation caused by smoking in lung parenchyma, pulmonary blood malities have been attributed to factors such as lifestyle, a reduc-
vessels and the airways [136] . In either case, and indeed they prob- tion in food intake [156] , an increase in metabolic costs [53] and,
ably coexist, inflammation will affect systemic circulation reach- more recently, the presence of systemic inflammation [27,157] and
ing various organs (including muscles) and contributing to their changes in the metabolism of certain substances, such as leptin
dysfunction [137,138] . An intriguing question is what causes the [156] . Nutritional status is a good predictor of mortality in COPD
inflammatory response to persist after the initial noxious stimulus and lung cancer patients [131,158] and can influence their mus-
has disappeared. Current thinking on the answer to this ques- cles. Specifically, malnutrition results in decreased muscle mass,
tion is based on the hypothesis that these mechanisms may be changes in fiber type percentages and muscle dysfunction [159,160] .
immunological [139] .
Comorbidity & aging
Inflammation The increased life expectancy in developed societies has resulted
There is overwhelming evidence to support the hypothesis that in a high percentage of elderly patients [161] . In addition, as a con-
a certain level of systemic inflammation is present in COPD [52] . sequence of the etiopathogenic factors shared by respiratory con-
It has been shown that serum levels of certain inflammatory ditions and other disorders, comorbidity is frequently observed.
biomarkers (C-reactive protein, fibrinogen and several cytokines) In these circumstances, muscle dysfunction has been attributed
are elevated in these patients [27,137] , and higher white blood cell to sarcopenia, characteristic of elderly subjects, and to abnor-
counts have also been found [137,140] . Moreover, it has recently malities in muscle function also present in highly prevalent dis-
been suggested that the systemic manifestations of COPD may be eases, such as chronic heart failure, diabetes and rheumatological
an expression of an attenuated form of the systemic inflammatory diseases [46,162,163] .
response syndrome [141] . This syndrome has traditionally been
conceptualized in the context of the multiorgan failure associ- Extreme sedentarism
ated with sepsis [112], but could also be present in a minor form in This is very common in developed countries and leads to cardio-
other chronic conditions, such as COPD [141,142] , cystic fibrosis vascular and muscle deconditioning. In fact, the level of physical
[105] or asthma. Systemic inflammation can have important effects activity, which is the determinant for an appropriate muscle phe-
on muscles: various cytokines can induce an increase in local notype, is a prognostic factor for exacerbations and even for life
protein degradation through oxidative stress or the activation expectancy in patients with COPD [164–166] . However, this factor
of proteolytic pathways [143,144] , both found in COPD muscles seems to be especially important in peripheral muscles because
[29,59,145,146] . Furthermore, certain proinflammatory cytokines the activity of respiratory muscles would even be even increased
can inhibit muscle contraction [147] , although they appear to be in sedentary individuals with respiratory disorders.
necessary for muscle repair [148] .
Gas-exchange abnormalities
Oxidative stress Hypoxemia and hypercapnia are frequently observed in many
This is closely related to inflammatory mediators, which in respiratory diseases and can result in a decrease in muscle strength
conjunction with other factors also present in chronic diseases, or endurance [167–169] . Hypoxemia can reduce oxygen delivery to
such as COPD, lead to oxidative and nitrosative stress [8,149,150] . the muscle. This reduction will be even higher in the presence of
Inversely, the stress can act as a signal for increased expression anemia, a circumstance also very prevalent in chronic diseases,
such as COPD. If tissue hypoxia develops it can result in a reduc- Their major adverse effect is a myopathy, mainly characterized
tion in stored energy and protein synthesis, impairing muscle con- by rhabdomyolysis and intense muscle pain, that initiates in the
traction [170–172] . In a similar way the presence of hypercapnia will arms and thighs [183,184] . Note that drugs, such as macrolides,
affect muscle contractility, both directly and indirectly, through frequently used in exacerbations of COPD, interact with statins
the development of muscle acidosis [167,173] . and can augment their effects [183] .
Diuretic drugs can lead to electrolytic imbalance, which in turn
Treatments commonly used in respiratory disease can deteriorate muscle function. In this regard, abnormalities
patients in the plasma levels of Na+, K+, Cl- and other ions can result in
Corticosteroids can induce both acute and chronic myopathies, impaired contraction and easier fatigability.
mostly when used systemically [174] . Although the use of sys- Phosphodisterase 5 inhibitors augment cyclic GMPc by inhibit-
temic corticosteroids has declined considerably, these agents are ing a key enzyme, which results in smooth muscle relaxation and
still necessary in the management of certain seriously ill patients. vasodilation. Therefore, they are being used for pulmonary hyper-
Corticosteroids also appear to be used more liberally in certain tension and erectile dysfunction [183,184] . Some of these drugs have
European countries and in North America, perhaps owing to the also been shown to inhibit the muscle effects of insulin (capillary
particular characteristics of the health systems in those countries. recruitment and glucose uptake) [189] , which might result in early
Acute myopathy can develop following administration of high doses muscle fatigue. However, there is also some evidence in animal
of corticosteroids [175] and is characterized by marked weakness that models that phosphodisterase 5 inhibitors might ameliorate
can affect various muscle groups [176] . The structural bases of this muscle damage in muscle dystrophy [190] .
functional impairment are the loss of myosin filaments and rhab-
domyolysis [177,178] . Chronic myopathy in turn is the consequence Expert commentary
of long-term administration of steroids, even at relatively low doses Respiratory disorders (e.g., COPD, bronchial asthma and thoracic
[179] . It is mainly characterized by muscle weakness in proximal deformities) and their treatments (drugs and mechanical ventila-
muscle groups (girdles and trunk) [179] . Cellular and biochemical tion) are frequently associated with respiratory and/or limb mus-
abnormalities underlying chronic myopathy include type II fiber cle dysfunction. Whereas respiratory muscle dysfunction results
atrophy, an imbalance in protein synthesis and degradation, and in ventilatory problems, limb muscle dysfunction leads to a reduc-
abnormalities in carbohydrate metabolism [179,180] . tion in exercise tolerance and limitation of many everyday tasks.
Anticholinergics are used in respiratory patients as bronchodi- Muscle dysfunction is attributed to the complex interaction of
lators to block muscarinic receptors of acetylcholine, and thus general and local factors, including inflammation, oxidative stress,
relax airway smooth muscles. Although their effects on skeletal comorbidities, drugs, increases and decreases in muscle activity
muscles are irrelevant at standard doses, higher levels can impair and changes in thorax geometry. Greater knowledge about the
diaphragm contraction [181] and reduce muscle reaction time [182] . causes and consequences of the muscle dysfunction that occurs
b-blockers are competitive antagonists of b-adrenergic receptors in respiratory disorders would open new therapeutic strategies,
and are widely used in cardiovascular disorders, such as hyper- including a more rational use of current drugs and muscle train-
tension and ischemic heart disease. Since many patients with ing, and perhaps, to the adoption of new antioxidants, NSAIDs,
respiratory diseases also present these comorbidities, they fre- anabolic agents and calcium sensitizers as they become available.
quently receive systemic b-blockers. This occurs even in subjects
also receiving inhaled b-agonists. b-blockers decrease myocardial Five-year view
contractility [183,184] and have also been shown to facilitate skeletal There are good reasons to believe that the next few years will
muscle fatigue [185] , although they do not appear to reduce skeletal bring not only increased knowledge about the mechanisms of
muscle strength [186] . muscle dysfunction in respiratory diseases but also new therapeu-
Calcium channel blockers inhibit channels that mediate the tic approaches to the management and treatment of muscle dys-
entry of extracellular Ca 2+ into muscle cells. Calcium channel function. In this respect, recent conceptual advances have opened
blockers are extensively used in respiratory patients with cardio- the way to optimizing classical instruments. These include the
vascular comorbidities (systemic hypertension, angina pectoris expanded use of rehabilitation programs. Although rehabilitation
and so on) and have negative inotropic effects on myocardium. is indicated in many COPD guidelines [191,301] , the actual use of
However, this effect has not been described for skeletal muscles. this integral therapy is still relatively limited. However, particularly
Nevertheless, there is some evidence about the action of calcium when it involves muscle and general exercise training, rehabilitation
channel blockers on attenuation of contraction-induced muscle has a considerable effect, not only on muscle function, but also on
damage [187] and the differentiation of muscle myoblasts/satel- reduction of exacerbations and improved exercise tolerance, quality
lite cells [188] . This could have some negative influence in the of life and even patient survival [51,192–194] . This can be applied, not
remodeling process undergone by respiratory muscles in obstruc- only to COPD, but also to many other respiratory conditions, such
tive diseases, but might also attenuate the progression of some as cystic fibrosis and scoliosis. It is important to note, however, that
myopathies. not all COPD patients will respond to muscle training. In the more
Statins are widely used for dyslipidemia because they inhibit advanced stages of the disease, when nutritional abnormalities
an enzyme that catalyzes an early step in cholesterol biosynthesis. become very relevant and/or exacerbations are extremely frequent,

these subjects would need additional measures in order to restore structure and function [204] . Other drugs widely used in patients
even minimal performance. Noninvasive MV, a technique that with cardiovascular disorders, such as angiotensin-converting
is already well accepted in the management of COPD exacerba- enzyme inhibitors, have been shown to prevent cachexia and
tions and restrictive disorders, could also prove to be useful in improve muscle strength [205,206] . More recently, calcium sensi-
selected stable patients with obstructive diseases. However, this will tizers, widely used in chronic heart failure, have demonstrated
depend on better identification of the most appropriate candidates their ability to improve contractility of diaphragmatic fibers from
[141,195] : those in whom ventilatory support allows the muscles the COPD patients, as well as respiratory muscle function of healthy
rest they need. In addition, it should be taken into account that individuals [207] . This finding opens new perspectives for drug
mechanical ventilation can also have deleterious effects on muscle management of muscle dysfunction in the near future. In addition,
function in specific groups of patients. The administration of drugs surgical and endoscopic procedures can result in reductions of lung
with anabolic, anti-inflammatory or antioxidant properties can volume that reshape the diaphragm in COPD, thus restoring its
be expected to increase dramatically in the coming years [152,196] . mechanical properties [208,209] . Although these procedures are still
Specifically, nutritional supplements, testosterone and other ana- only used in very specific patients, it is to be expected that new
bolic agents appear to have a beneficial effect on muscle mass, techniques will extend their use.
muscle strength, quality of life and survival in particular groups Finally, we should not forget that tobacco smoking is known
of patients [154,197,198] . For example, the use of nutritional support to negatively influence muscle function in respiratory diseases.
has been shown to be beneficial in subjects who have lost weight. Health policies that have been implemented in many countries
One novel prospect is the potential use of ghrelin (a growth hor- to eradicate smoking, along with measures devoted to increasing
mone secretagogue) and growth factors similar to those produced the level of physical activity, are expected to definitively decrease
by healthy muscle during training (mechano growth factor) [199] muscle dysfunction as a complication for our respiratory patients.s
or substances inhibiting myostatin [200] . By contrast, drugs with
anti-inflammatory properties should be used with more caution, Acknowledgement
since some of the proinflammatory cytokines have dual effects on The authors would like to acknowledge Elaine Lilly, PhD, for editing help.
the muscles. On the one hand, they can cause damage and impair
contraction, but on the other they appear to be necessary for muscle Financial & competing interests disclosure
growth and regeneration [201,202] . Since one of the factors impli- Funded, in part, by CIBERES ISC III, Plan Nacional SAF2007-62719
cated in muscle dysfunction is oxidative stress, it is not surprising and FUCAP. The authors have no other relevant affiliations or financial
that there is increased evidence on the potentially beneficial effects involvement with any organization or entity with a financial interest in or
on muscles of antioxidants, such as N-acetylcysteine, vitamin E financial conflict with the subject matter or materials discussed in the
and a-tocopherol [152,203] . Another active research field studies the manuscript apart from those disclosed.
use of nonsteroidal anti-inflammatory agents to modulate muscle No writing assistance was utilized in the production of this manuscript.
Key issues
• Muscle dysfunction is frequent in many disorders targeting the respiratory system. These include chronic obstructive pulmonary
disease, chronic asthma, obstructive sleep apnea syndrome, cystic fibrosis, lung cancer, thoracic deformities and neuromuscular
disorders.
• Respiratory muscle dysfunction results in hypoventilation and can lead to death. It can also hamper the weaning process in
mechanically ventilated patients. Peripheral muscle dysfunction results in exercise limitation and restrictions in many daily activities.
• Muscle dysfunction associated with chronic obstructive pulmonary disease is probably the result of the complex interaction between
local and systemic factors. While pulmonary hyperinflation appears to be the main factor contributing to respiratory muscle
dysfunction, deconditioning is believed to play a determinant role in peripheral muscle dysfunction.
• Drugs typically used in respiratory disorders, including corticosteroids, b-blockers and diuretics, can impair muscle function.
• A wider and better use of both rehabilitation programs and noninvasive mechanical ventilation, as well as appropriate nutritional
support and pharmacological strategies (antioxidants, nonsteroidal anti-inflammatory agents, growth factors and calcium sensitizers),
will open new possibilities in the treatment of muscle dysfunction.
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contribute to reduce both the strength and

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intensity of the functional impairment is

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References 2 Orozco-Levi M, Gea J, Lloreta J et al. 4 Barreiro E, de la Puente B, Minguella J

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