upper limb muscle dysfunction executive summary

AMERICAN THORACIC SOCIETYDOCUMENTS

An Official American Thoracic Society/European RespiratorySociety Statement: Update on Limb Muscle Dysfunctionin Chronic Obstructive Pulmonary DiseaseExecutive SummaryFrançois Maltais, Marc Decramer, Richard Casaburi, Esther Barreiro, Yan Burelle, Richard Debigare,P. N. Richard Dekhuijzen, Frits Franssen, Ghislaine Gayan-Ramirez, Joaquim Gea, Harry R. Gosker, Rik Gosselink,Maurice Hayot, Sabah N. A. Hussain, Wim Janssens, Michael I. Polkey, Josep Roca, Didier Saey,Annemie M. W. J. Schols, Martijn A. Spruit, Michael Steiner, Tanja Taivassalo, Thierry Troosters, Ioannis Vogiatzis,and Peter D. Wagner; on behalf of the ATS/ERS Ad Hoc Committee on Limb Muscle Dysfunction in COPD

THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) AND THE EUROPEAN RESPIRATORY SOCIETY (ERS) WAS APPROVED BY THE ATS BOARD OF

DIRECTORS, NOVEMBER 2013, AND BY THE ERS EXECUTIVE COMMITTEE, SEPTEMBER 2013

Background: Limb muscle dysfunction is prevalent in chronicobstructive pulmonary disease (COPD) and has important clinicalimplications, such as reduced exercise tolerance, quality of life, andeven survival. Since the last American Thoracic Society (ATS)and European Respiratory Society (ERS) statement on limbmuscle dysfunction, important progress has been made in thecharacterization of this problem and on our understanding of itspathophysiology and clinical implications.

Purpose: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.

Methods: An interdisciplinary committee of experts from the ATSand ERS determined that the scope of this document should belimited to limb muscles. Committee members conducted focusedreviews of the literature on relevant topics. A librarian also performeda literature search. An ATS methodologist provided advice to thecommittee, ensuring that the methodological approach wasconsistent with ATS standards.

Results:We identified important advances in our understanding ofthe extent and nature of the structural alterations in limb musclesin patients with COPD. Since the last update, studies have beenpublished regarding mechanisms of development of limb muscledysfunction in COPD and on the treatment of this condition.The clinical implications of limb muscle dysfunction have beendelineated.Although exercise training is themost potent interventionto address this condition, other therapies, such as neuromuscularelectrical stimulation, are emerging. Assessment of limb musclefunction can identify patients who are at increased risk of poorclinical outcomes, such as exercise intolerance and prematuremortality.

Conclusions: Limb muscle dysfunction is a key systemicconsequence of COPD.However, there are still important gaps in ourknowledge about mechanisms of development of this problem.Strategies for early detection and specific treatments for thiscondition are needed.

This Executive Summary is part of the full official Limb Muscle Dysfunction in COPD Update statement, which readers may access online at www.atsjournals.org/doi/abs/10.1164/rccm.201402-0373ST. Only the Executive Summary is appearing in the print edition of the Journal. The article of record, and the one that shouldbe cited, is: An Official American Thoracic Society/European Respiratory Society Statement: update on limb muscle dysfunction in chronic obstructive pulmonarydisease. Am J Respir Crit Care Med 2014;189:e15–e62. Available at www.atsjournals.org/doi/abs/10.1164/rccm.201402-0373ST.

F.M. holds a CIHR/GSK Research Chair on COPD at Universite Laval. R.C. holds the Grancell/Burns Chair in the Rehabilitative Sciences. E.B.’s contribution tothis statement was supported by CIBERES, FIS 11/02029, 2009-SGR-393, SEPAR 2010, FUCAP 2011, FUCAP 2012, and Marato TV3 (MTV3-07-1010)(Spain) and by the ERS COPD Research Award 2008. M.I.P.’s contribution to this statement was supported by the NIHR Respiratory Disease BiomedicalResearch Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, who partially fund his salary.

Am J Respir Crit Care Med Vol 189, Iss 9, pp 1121–1137, May 1, 2014

Copyright © 2014 by the American Thoracic Society

DOI: 10.1164/rccm.201402-0373ST

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American Thoracic Society Documents 1121

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Contents

OverviewIntroductionMethodsScope and DefinitionLimb Muscles in Clinically StableCOPD

Muscle AtrophyStructural AlterationsMitochondrial Function andBioenergetics

Oxidative StressLimb Muscle Function

Limb Muscle Function during COPDExacerbation

Consequences of LimbMuscle Dysfunction in COPD

Etiology of Limb Muscle Dysfunctionin COPD

Disuse versus MyopathyMechanisms of Limb MuscleDysfunction in COPD

Assessment of LimbMuscle Functionin COPD

Effects of Interventions on LimbMuscle Function in COPD

Exercise TrainingOther Interventions

Suggestions for FutureResearch

Conclusions

Overview

Limb muscle dysfunction is an importantsystemic consequence of chronic obstructivepulmonary disease (COPD) because ofits impact on physical activity, exercisetolerance, quality of life, and even survival.Although some mechanisms underlyingdevelopment of limb muscle dysfunctionhave been identified (e.g., deconditioning),much needs to be learned about the impactof other potential contributors to this clinicalmanifestation of COPD. Limb muscledysfunction can be prevented and improved,in part, with exercise training, but it is clearthat novel therapies are needed to betteraddress this problem.

The purpose of this document is toupdate the 1999 American Thoracic Society/European Respiratory Society (ATS/ERS)statement on limb muscle dysfunction. Weintend to provide researchers and clinicianswith recent advances in this field, withemphasis on the following areas: (1)

structural and metabolic alterations foundin limb muscles, (2) consequences andclinical evaluation of limb muscledysfunction, (3) mechanisms ofdevelopment of this comorbidity, and (4)treatment approaches to limb muscledysfunction in COPD. Future researchdirections are also discussed.

Major conclusions of the statementinclude:

d Limb muscle dysfunction is prevalent inCOPD. Muscle atrophy and weaknesscarry important consequences, such asdifficulties in engaging in physical activity,exercise intolerance, poor quality of life,and premature mortality. Metabolicalterations in relation to structuralchanges within the lower limb muscle arealso involved in exercise limitation.

d Lower limb muscle function is furthercompromised during COPDexacerbations. Patients experiencingexacerbations may be targeted forrehabilitative interventions aiming atpreserving limb muscle function.

d Assessment of limb muscle functionshould be encouraged.

d Knowledge of the biochemical regulationof muscle mass will likely lead todevelopment of specific therapy formuscle atrophy in COPD.

d Although physical inactivity is involvedin the development of limb muscledysfunction development in COPD,other mechanisms, such as inflammation,oxidative stress, nutritional imbalance,and hypoxemia, likely play a role.

d The most potent currently availabletreatment option for limb muscledysfunction is exercise training, a keycomponent of integrated COPDmanagement.

d Neuromuscular electrical stimulation isemerging as a useful training modality inseverely impaired COPD and duringexacerbations.

Introduction

Limb muscle atrophy and weakness areprevalent in COPD, affecting up to one-third of patients with COPD seen inspecialized centers (1–3). Furthermore, thisproblem is not only confined to advanceddisease; it may also occur in mild COPD(3). More than 10 years have elapsed since

the first ATS/ERS statement on limbmuscles in COPD (4). Since then, abundantevidence shows that limb muscle atrophyand weakness are strongly related toexercise intolerance, quality of life, andeven premature mortality in COPD(1, 5–7). Another emerging message is thatCOPD exacerbations are associated withfurther decreases in quadriceps strengthand mass (8–10). This finding is relevantbecause the preservation of muscle strengthcould become an important treatment goalduring COPD exacerbation.

The involvement of limb muscles inCOPD goes beyond simple issues of atrophyand weakness. Important morphological andmetabolic alterations have been reported inthis condition at rest and during exercise. Thesechanges lead to premature use of glycolyticmetabolism in the contracting muscles andpromote muscle fatigue and exerciseintolerance (11–13). Together, muscle atrophyand weakness as well as morphological andmetabolic alterations are components of limbmuscle dysfunction in COPD.

Limb muscle weakness and atrophy inCOPD are likely of multifactorial origin, butlittle is known about the interplay and therelative role of the mechanisms underlyingthe phenomena. Molecular and biochemicalmechanisms involved in muscle massregulation in COPD are emerging (14–18).This line of research will, we hope, leadto development of specific therapies formuscle atrophy in COPD. As it stands now,exercise training remains the most potenttherapeutic intervention to improve limbmuscle function in COPD.

The primary objective of this documentis to update current scientific and clinicalknowledge on this topic and to provideguidance for future research directions. Thisdocument should be useful to scientists andalso to clinicians, for whom we wish toraise awareness regarding the clinical relevanceof limb muscle dysfunction.

Methods

The present document is intended to bea Clinical Statement. Methods involved in theproduction of this document are summarizedin Table 1 and in the full document (online).

Scope and Definition

This document focuses on limb muscles, ascommittee members agreed that respiratory

AMERICAN THORACIC SOCIETY DOCUMENTS

1122 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 9 | May 1 2014

muscles are a separate topic. Limb muscledysfunction is used in this document toreflect morphological and functionalchanges seen in limb muscles in patientswith COPD with no implications onunderlying mechanisms.

Limb Muscles in ClinicallyStable COPD

Several structural changes of the limbmuscles have been reported in patients withCOPD. They are described in this sectionand summarized in Figure 1. In comparisonto the quadriceps, upper limb muscles arerelatively spared.

Muscle AtrophyUsing World Health Organizationclassification for body mass index (BMI),underweight in COPD is found in up to 30%of patients with Global Initiative forChronic Obstructive Lung Disease (GOLD)class 4 COPD (2). Studies assessing bodycomposition revealed that reduced musclemass occurs in 4 to 35% of patients withCOPD (2, 19, 20), this proportion beingdependent on the criteria used to definelow muscle mass (1, 2, 21). Low fat-freemass index (FFMI) is reported in 26% ofpatients with COPD with a normal BMI,underscoring the importance of assessingbody composition to quantify preciselymuscle atrophy (2). Even in the presenceof a normal BMI, low FFMI is a strong

predictor of mortality (1). Lower limbmuscles are particularly vulnerable toatrophy in COPD (22, 23).

Structural Alterations

Muscle fiber atrophy and fiber type shift. Allfiber types of the quadriceps are affected bythe atrophying process (24), although someauthors argue that the type IIx fibers aremore specifically affected (25–27). A shiftin quadriceps fiber type distribution, fromtype I to type IIx fibers, is a typical featureof advanced COPD (23, 24, 28, 29). Thisfinding is inconsistent with normal aging,which is not associated with a shift towardtype II fibers (30, 31). The proportion oftype I fibers correlates inversely withdisease severity (32, 33). The fiber typedistribution shift in quadriceps and tibialisanterior (34) muscles is not observed inupper extremity muscles (35), indicatingthat muscle structural abnormalities are nothomogeneously distributed among musclegroups.

Changes in capillarization. Totalnumbers of capillaries and capillariesper muscle fibers are reduced in limbmusclesof COPD (24, 36). This is not a universalfinding (37), perhaps because, in somestudies, patients were involved in exercisetraining, which could improve musclecapillarization (38). However, reduction inthe capillary to muscle fiber cross-sectionalarea has not been reported (39).

Mitochondrial Functionand BioenergeticsMitochondrial functionality is altered inCOPD limb muscles (38). Locomotormuscle oxidative capacity is reduced inCOPD (40, 41), and this is consistentwith type I to type IIx fiber type shift foundin COPD (24, 28). Limb muscle metabolicprofile of patients with COPD shows,at rest, low levels of ATP, inosinemonophosphate, and phosphocreatinelevels compared with age-matched healthycontrol subjects (41, 42). Half-timephosphocreatine recovery after cyclingexercise is slower and phosphocreatineto inorganic phosphate ratio is lower inCOPD than in healthy control subjects(43). In addition, intermediate markers ofglycolysis as well as phosphofructokinaseand lactate dehydrogenase activitiesare elevated in resting COPD muscles(41, 44, 45).

Oxidative StressEvidence of oxidative stress with higherlevels of lipid peroxidation, oxidizedglutathione, and protein oxidation andnitration is consistently found in the bloodand limb muscles of patients with COPD(17, 27, 32, 46–64), particularly those withmuscle atrophy (65). The development ofoxidative stress in limb muscles of patientswith COPD may result from enhancedinflammatory cell infiltration and cytokineproduction. However, there is no strongrelationship between muscle oxidativestress and muscle inflammation in patientswith COPD (17, 27, 52, 62, 64). Muscleoxidative stress may also be related tomitochondrial dysfunction. Interestingly,chronic cigarette smoke exposure alsoinduces a significant increase in severaloxidative stress markers in limb muscles ofhealthy smokers (17) and in limb musclesof animals chronically exposed to cigarettesmoke (17, 66).

Limb Muscle FunctionStrength and endurance are the two maindefining features of muscle function; theycan vary independently in such a way thatone cannot be used to predict the other (67).Strength refers to the ability of the muscleto generate force; endurance is defined asthe ability of the muscle to sustain a giventask. Muscle weakness and reducedendurance are frequent in COPD.Quadriceps strength is reduced by anaverage of 20 to 30% in these individuals

Table 1: Methods

Methods Checklist Yes No

Panel assemblyIncluded experts from relevant clinical and nonclinical disciplines XIncluded individual who represents views of patients and societyat large

X

Included methodologist with documented expertise XLiterature reviewPerformed in collaboration with librarian XSearched multiple electronic databases XReviewed reference lists of retrieved articles X

Evidence synthesisApplied prespecified inclusion and exclusion criteria XEvaluated included studies for sources of bias XExplicitly summarized benefits and harms XUsed PRISMA (252) to report systematic review XUsed GRADE (253) to describe quality of evidence X

Generation of recommendationsUsed GRADE to rate the strength of recommendations X

Definition of abbreviations: GRADE = Grading of Recommendations Assessment, Development andEvaluation; PRISMA = Preferred Reporting Items for Systematic reviews and Meta-Analyses.



(3, 8, 10, 54, 67–80), and weakness isfound in patients with mild disease (3).Conflicting data exist about the rate ofdecline in quadriceps strength in patientswith COPD, which was reported to beincreased (8) or similar to the healthyaging population (81). Muscle weaknessis not similar among muscle groups:strength of the upper limb muscle isbetter preserved than that of lower limbmuscles (35, 70, 82). Muscle weakness isa direct consequence of reduced musclemass (54, 68, 71, 83, 84), althoughduring chronic or repeated exposure tosystemic corticosteroids, strength lossout of proportion to muscle massreduction can occur (68, 85).

Muscle endurance and fatigue. Volitional(57, 59, 67, 73, 86–89) and nonvolitional(90) quadriceps endurance is decreased inCOPD. Magnitude of decrease is highly

variable (range, 32–77%), probablybecause of differences in test procedures.Impaired quadriceps endurance is alsopresent in patients with mild to moderateCOPD, even in those with relativelynormal physical activity (67). Impairedquadriceps endurance is the consequenceof reduced oxidative capacity andoxidative stress (73), rather than reducedmuscle mass (83). Endurance of theupper extremity muscles (69, 74, 91) ispreserved in patients with COPD,providing additional indication aboutheterogeneity of muscle abnormalities inthis disease.

Fatigue is defined as a failure of forcegeneration after loaded muscle contractionsthat is reversible by rest (87, 92). Quadricepsfatigue can be objectively demonstrated in48 to 58% of patients with COPD aftercycling exercise (6, 72, 79, 93). Taking into

account the amount of work performed, thesepatients exhibit greater susceptibility tofatigue than healthy individuals (72).The gastrocnemius and tibialis anteriorof patients with COPD may also be moresusceptible to fatigue during walking(80, 94). Susceptibility to muscle fatiguein COPD can be related to intrinsicmuscle morphometric and metabolicderangements seen during exercise in thisdisease (11,13, 95–97). Insufficientoxygen delivery to contractile muscle mayalso contribute to premature lower limbmuscle fatigue (98, 99).

Limb Muscle Function duringCOPD Exacerbation

Quadriceps strength often decreases duringhospitalization for COPD exacerbation(10, 100, 101). Reduction in quadriceps

Figure 1. Morphological and structural alterations reported in limb muscles in patients with chronic obstructive pulmonary disease (COPD). CS = citratesynthase; HADH = 3-hydroxyacyl CoA dehydrogenase.



force during hospitalization is associatedwith less improvement in walking time1 month after discharge (100). Importantly,quadriceps force only partially recovered3 months after hospital discharge (10).Muscle weakness has been associated withincreased risk of hospital readmissionsdue to acute exacerbation (102). Musclemass and strength maintenance may becompromised during an exacerbation,with activation of multiple atrophyingbiochemical pathways during this process(101, 103). Causes of muscle dysfunctionduring exacerbations may involveinflammation (10), impaired energybalance (104, 105), inactivity (100, 106),and systemic corticosteroid use (85).

Consequences of LimbMuscle Dysfunction in COPD

The most troublesome consequence ofmuscle dysfunction is its association with

reduced life expectancy (1, 5, 7) (Figure 2).Muscle atrophy (1, 5) and quadricepsweakness (7) are predictors of mortality insubjects with COPD: (1) midthigh musclecross-sectional area less than 70 cm2 asassessed by computed tomographyscanning is associated with fourfoldincrease in mortality after adjusting forage, sex, and FEV1 (5); (2) FFMI less than16 kg/m2 in men and less than 15 kg/m2 inwomen is associated with 1.9-fold increasein mortality after adjusting for age, sex, andFEV1 (1); and (3) a quadriceps strength(kg) to BMI (kg/m2) ratio less than 120%is associated with increased mortality; each10% increment of this ratio is associatedwith a 9% reduction in mortality (7). Theseindicators stress the importance forclinicians to carefully monitor bodycomposition and muscle strength inpatients with COPD. Muscle atrophy andweakness are also associated with reducedquality of life (107) and greater healthcare

resource use (108). Quadriceps strengthis a strong predictor of exercise capacity inpatients with pulmonary diseases (109):a twofold increase in muscle strength isassociated with 1.4- to 1.6-fold increase inwork capacity (110). One explanation forthis is the influence of muscle strengthon leg effort perception during exercise(110), the main limiting symptom in anappreciable portion of patients withCOPD (111) (Figure 2). Premature legfatigue reduces the ability ofbronchodilators to produce improvementin exercise tolerance (6, 112).Perturbation in muscle energymetabolism during exercise seen inCOPD is also relevant to whole-bodyexercise capacity, as it is associated withpremature fatigue (11, 13, 95–97) andincreased ventilatory requirements duringexercise (46, 113, 114), imposing anadditional burden on already overloadedrespiratory muscles.

Figure 2. Relationships between muscle mass and strength and clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). Amidthigh muscle cross-sectional area (MTCSA), 70 cm2 (A) (5), a low fat-free mass index (FFMI) defined as an FFMI , 16 kg/m2 in men and , 15 kg/m2

in women (B) (1), and a reduced quadriceps strength defined as a quadriceps strength (kg) to body mass index (BMI, kg/m2) ratio , 120% (C) (7)are predictors of mortality in COPD after adjusting for traditional mortality risk factor such as age and FEV1. The strength of the quadriceps is a significantcontributor to exercise capacity in COPD (D) (110). All panels adapted by permission from the indicated references.



Etiology of Limb MuscleDysfunction in COPD

Several factors have been hypothesized toinitiate and/or promote changes in limbmusclesof patients with COPD (Table 2). Together,they have the ability to activate variousbiochemical pathways initiating or enhancingalterations in fiber type expression, contractileproteolysis, metabolic alterations, andregenerative defects in limb muscles.

Disuse versus MyopathyOne important question is whether limbmuscle dysfunction simply reflects years of

physical inactivity or whether some COPD-specific myopathy (115–119) can beinvoked. Against the hypothesis of COPDmyopathy are observations that manyfunctional and cellular findings in COPDare identical to those of disuse and thatlimb muscle function and oxidative profilecan be improved with training (115, 118,120–124). The fact that full recovery ofmuscle function is unusual does notnecessarily indicate a myopathy, becauseintensity and/or duration of training maybe insufficient to correct alterations thathave developed over several decades (119,125, 126). On the other hand, several

observations favor the existence ofa myopathy in patients with COPD. Musclestructure and function are poorly related tothe degree of physical activity (127–129).Disparities in muscle function and/orstructure remain when patients with COPDare compared with control subjectshaving similar degree of physical activity(116, 130). Muscle typology does notimprove to the same extent after exercise inCOPD (24, 131, 132) compared withhealthy subjects (133–135).

Mechanisms of Limb MuscleDysfunction in COPD

Inflammation. Through transcriptionalactivities of nuclear factor-kappa B (NF-kB)and forkhead box O (FOXO) (136),production of proinflammatory cytokinesduring the inflammatory response canenhance ubiquitin proteasome systemactivity, apoptosis (137), andmacroautophagy occurrence (138), whichhave all been linked to muscle atrophydevelopment (139, 140). Increasedexpression of E3-ligases Atrogin-1, musclering finger protein 1 (MuRF-1), and neuralprecursor cell expressed developmentallydown-regulated protein 4 (Nedd4) isobserved in quadriceps of patients withCOPD (14, 15). Despite these convincingarguments supporting a role forinflammation, data supporting its presencein quadriceps of patients with COPD areequivocal (45, 52, 141–144), even inestablished muscle atrophy and duringperiods of acute exacerbation wheninflammatory bursts should be expected(103).

Oxidative stress. In COPD, systemic(56) and local (27, 48, 49) oxidative stresshas been reported at rest, during acuteexercise bouts (54, 56), and during acuteexacerbation (145, 146). Oxidative stresslevels are directly related to quadriceps forceand endurance in patients with severeCOPD (17, 52, 53, 57, 59). Oxidative stresscould alter the integrity of proteins,enhancing their degradation (147). Directoxidative stress exposure (148) or indirectproduction of reactive oxygen speciesthrough inflammatory response (149, 150)induces proteolysis and increases expressionof ubiquitin-proteasome components.Induction of NF-kB (149) and FOXO (151)transcriptional activities or p38 kinaseactivity (18, 152) by oxidative stress arebelieved to regulate proteolytic signaling.

Table 2: Etiologies of Limb Muscle Atrophy, Weakness, and Susceptibility to Fatigue

Mechanisms Involved

Factors leading to muscle atrophy andweakness

Disuse Associated with weakness, atrophy,changes in fiber type distribution andmetabolic alterations (118, 120–123)

Inflammation Triggering of the muscle proteolysiscascade (14, 15, 139, 140)

Oxidative stress Triggering of the muscle proteolysiscascade (147, 149, 150)

Associated with reduced muscleendurance (51, 57, 59)

Protein carbonylation possibly involved inexercise intolerance and weakness (55)

Hypoxemia Decreased muscle protein synthesisActivation of muscle degradation throughhypoxia-inducible factor/vonHippel–Lindau signaling cascade(158, 254–256)

Hypercapnia Intracellular acidosis/alterations incontractile protein synthesis/degradation(163, 164)

Low levels of anabolic hormones andgrowth factors

Associated with reduced muscle proteinsynthesis (257, 258)

Impaired energy balance Associated with reduced muscle proteinsynthesis (175, 259)

Corticosteroids Reduced muscle protein synthesis andenhanced proteolysis through increasedmyostatin levels and reduced insulin-likegrowth factor-1 levels (178)

Vitamin D deficiency Associated with muscle weakness, type IIatrophy impaired calcium metabolism(180, 184, 260)

Factors leading to muscle susceptibilityto fatigue

Central fatigue—afferent feedback fromlimb muscles

Reduced motor output to the contractingmuscles (261)

Reduced O2 delivery (impaired cardiacoutput, blood flow competitionbetween the respiratory and limbmuscle, reduced capillarity)

Changes in muscle metabolism in favor ofglycolysis; accumulation of musclemetabolites associated with musclefatigue

Muscle metabolic alteration (reducedoxidative enzyme activity, reducedmitochondrial function)

Preferential use of glycolysis andaccumulation of muscle metabolitesassociated with muscle fatigue (45, 96,262–264)



Hypoxia. Hypoxic conditions decreasemuscle mass (153, 154). Patients withCOPD having reduced arterial PO2 (155)or O2 delivery (156) tend to have lowerbody mass than those with preservedoxygenation. Biochemical mechanismsinvolved in the negative muscle massregulation by hypoxemia are complex andinvolve hypoxia inducible factor-1 signalingcascade (157, 158). Both inflammatoryresponse (159) and increased productionof reactive oxygen species (59, 160) asa reaction to hypoxia have been hypothesizedto link hypoxia to cellular signaling yieldingmuscle atrophy. Hypoxemia also may alsocompromise muscle oxidative capacity andcapillarization (161).

Hypercapnia. Increase in cellularCO2 content in chronic hypercapniamay worsen in exacerbated patients.Consequently, tissue pH decreases (162)and acidosis can alter contractile proteinsynthesis and degradation (163). In muscletissue, acidosis increases expression ofgenes encoding proteins of the ubiquitin-proteasome pathway (164) and impairsinsulin/IRS/AKT signaling (165).

Low levels of anabolic hormones andgrowth factors. Low testosterone levelshave been reported in COPD (166–170).However, association of limb musclefunction indices with serum testosteronelevels in COPD is inconsistent acrossstudies (166, 169). Myostatin, atransforming growth factor-b (TGF-b)family member that acts as a negativeregulator of limb muscle growth (171, 172),may be elevated in blood and muscles inCOPD (16, 173, 174).

Impaired energy balance. Muscleatrophy may result from disturbed balancebetween energy expenditure and dietaryintake, which may affect muscle proteinsynthesis rate, thus creating an imbalancebetween protein synthesis and breakdown.Altered appetite regulation, oxidative stress,and systemic inflammationmay all contributeto loss in muscle tissue in COPD (175).

Corticosteroids. Although short-termexposure to systemic corticosteroids doesnot appear to compromise limb musclestrength and function (176), chronic orrepeated exposure can potentiate muscleatrophy and weakness (85, 177).Corticosteroids decrease protein synthesisand simultaneously promote proteindegradation (178). These actions on proteinsynthesis are believed to occur throughinhibition of key hypertrophic biochemical

pathways. Muscle protein degradation inthe context of corticosteroids exposureis related to activation of ubiquitin-proteasome and lysosomal systems, twomajor proteolytic pathways (178).

Vitamin D deficiency. Vitamin Ddeficiency is highly prevalent in COPDcompared with age-matched smokingcontrol subjects (179), and it is suggestedthat vitamin D deficiency could contributeto limb muscle dysfunction (180, 181).However, published evidence isunconvincing in this regard (182, 183). Inone study, genetic polymorphisms in thevitamin D receptor associated withquadriceps strength (184), indicating thatthe vitamin D pathway may affect muscleindependent of serum levels.

Smoking. Cigarette smoking is unlikelyto be the main mechanism involved in limbmuscle dysfunction in COPD because,in several studies, smoking history wasmatched in patients with COPD and healthycontrol subjects. However, smoking by itselfmay be associated with muscle atrophyand weakness in otherwise healthy subjects (3,64, 81, 185–188). Smoking is also associatedwith decreased type I fiber cross-sectionalarea, reduced type I fiber proportion, reducedcytochrome oxidase activity, increased lactatedehydrogenase activity, and higher level ofprotein oxidation in the quadriceps(189–191).

Assessment of Limb MuscleFunction in COPD

The existing relationships between limbmuscle mass and strength and importantclinical outcomes in patients with COPD(see previous section on the consequencesof limb muscle dysfunction) suggest thatassessing body composition and limbmuscle strength in the clinical evaluation ofCOPD can identify patients who are atincreased risk for exercise intoleranceand premature mortality. Bioelectricalimpedance and dual-energy X-rayabsorptiometry provide reasonably accurateassessment of body composition (192).Learning about limb muscle status mayhelp clinicians understand the mechanismsof exercise limitation in a given patient.Limb muscle strength assessment is alsouseful to prescribe adequate loads forresistance training. One strategy could be toevaluate body composition and quadricepsstrength at the time of referral to theexercise laboratory for assessment of

dyspnea and/or exercise tolerance. Someexercise laboratories implemented thispractice several years ago (110).

Various methodologies exist to measuremuscle strength (193), including handhelddynamometry (70, 194), the one-repetitionmeasurement (the maximum value thata patient can move over the full range ofmotion) (195, 196), and hydraulic resistances(68, 197). They are discussed morecompletely in the full document (online).

We favor using strain gauges tomeasure isometric maximal quadricepsstrength; this methodology could beimplemented in clinical practice to providereliable and reproducible measurements(198, 199) (Figure 3). The maximalvoluntary contraction force hashistorically been reported in kilograms,because weights are used to calibrate theapparatus. Force could also be reportedin Newtons, the product of force inkilograms and gravitational pull (9.81 m/s2).Maximal voluntary contraction force istypically reported as the best of threereproducible maneuvers. Isometric muscleforce can also be assessed on specificallybuilt computerized dynamometers (e.g.,Cybex or Biodex), but these devices areexpensive and not widely available. Onecurrent limitation of assessment ofquadriceps strength is that there are nowidely accepted reference values. Thiscould be circumvented by expressingquadriceps strength in kilograms asa percentage of BMI (7). Another limitationof volitional assessment of strength is itsdependence on patient cooperation.Nonvolitional assessment of limb musclestrength involves electrical or magneticstimulation of a peripheral nerve (6, 78).This technique is currently practiced onlyin research laboratories.

Effects of Interventions onLimb Muscle Function inCOPD

The effects of interventions designed toimprove limb muscle mass and function aresummarized in Table 3.

Exercise TrainingExercise training is the only interventionthat can be indisputably recommended fortreatment of limb muscle dysfunction inCOPD. Rehabilitative exercise trainingimproves limb muscle function and



morphology in patients with COPD (93,125, 126, 200–203). Endurance exercisetraining (either of interval or constant-loadmodality) improves the cross-sectional area(CSA) of all fiber types within the vastuslateralis muscle (24, 33, 204, 205). Inaddition, endurance training has beenreported to modify quadriceps muscle fibertype distribution in favor of type I fibers

(204–206). These morphological andtypological adaptations in limb musclefibers are not different across GOLD classes2 to 4 (33). Exercise training also shiftsmuscle energy metabolism from glycolyticto oxidative metabolism (41, 43).Phenotypical changes within limb musclesare accompanied by positive adaptations inmuscle mass regulating pathways (132, 196,

205, 206). Resistance exercise, alone or incombination with aerobic exercise, alsohelps to improve muscle mass and strengthin COPD (197, 201, 203, 207).

An important question is whether theresponse to exercise training is normal inCOPD. Muscle angiogenic and molecularresponse to training may be blunted inCOPD (208, 209); whether this is entirelyexplained by an insufficient trainingintensity is uncertain. Gene expressionresponse after endurance training inpatients with COPD differs from that seenin healthy sedentary subjects (210).Qualitatively, genes associated withoxidative stress, ubiquitin proteasome, andcyclooxygenase pathways are distinctlyinduced in COPD, potentially reflectingspecific molecular response of muscleto exercise and suggesting additionalmechanisms for exercise limitation (210).The occurrence of oxidative (61) andnitrosative (53) stress at the muscle levelhas been reported after exercise training;cachectic patients seem to be more prone tothis effect (211). However, the functionalsignificance of these observations is unclear(209), and exercise training is a safe andeffective intervention to treat limb muscledysfunction in COPD.

The magnitude of response topulmonary rehabilitation in COPD is highlyvariable among patients (212), and thereseems also to be a genetic component tothis phenomenon (213, 214). Patientsdeveloping quadriceps contractile fatigueduring training sessions show greatertraining effects in terms of functionalexercise capacity and health-related qualityof life than those who do not (215). Thisargues in favor of training intensity beingan important determinant of exercisetraining outcome (62, 113, 216).

Exercise training early after anexacerbation. Several interventions toprevent or counteract muscle impairmentduring episodes of exacerbation have beenconsidered (217). Resistance traininginitiated during the second day ofhospitalization may counteract limbmuscle dysfunction: quadriceps forceincreased by 10%, and 6-minute walkdistance improved at discharge (9). Thiswas associated with a more favorableanabolic/catabolic balance in muscle (9).Moreover, 1 month after discharge,functional status and muscle forceremained better in the group that trainedduring the exacerbation (9).

Figure 3. Standard operating procedure for isometric quadriceps strength assessment. During themaneuver, vigorous encouragement of the patient is needed. Patient is positioned in a standardizedfashion (typically sitting with knees and hips in 908 flexion or, less often, supine [3]). Maximal voluntarycontraction force (reported in kilograms or Newtons) can be reliably assessed as the best of threereproducible maneuvers. Maximal voluntary contraction is recorded as the maximal force that can bemaintained for 1 full second.



Neuromuscular stimulation. Transcutaneousneuromuscular electrical stimulation canbe particularly useful for severely disabledpatients with COPD (218, 219), as theload on the cardiopulmonary system is low(220). Indeed, it may even be consideredfor home use (221) and in patients whoare unstable (222). Increase in midthighmuscle and type II fiber CSA, decrease infiber type I CSA, change in fiber typedistribution in favor of type I fibers,decreased muscle oxidative stress, alongwith a more favorable anabolic to catabolicbalance have been reported (222–224).Larger trials are needed to clarify theoptimal stimulation parameters(frequency, intensity, and duration ofstimulation) and in which population thistraining option should be offered.

Other InterventionsSeveral interventions have beeninvestigated for their ability to improvelimb muscle mass and function (Table 3).These interventions have not reachedwidespread clinical application becauseof uncertain efficacy and potential ofadverse effects.

Nutritional supplementation has beeninvestigated in COPD (225, 226). As bodyweight gain is associated with improvedprognosis in COPD (227), efforts should bemade to establish appropriate treatmentsfor the underweight patients. A caveat isthat weight gain may predominantly consistof fat mass with little effect on limb musclemass and function (226, 228). Combination ofnutritional intervention with an anabolicstimulus, such as exercise training, is

warranted to ensure that nutritionalintervention impacts muscle mass andfunction (229). Patients with COPD arevulnerable to nutritional depletionduring an acute disease exacerbation.Adequate nutritional support, especiallyin patients with already impaired energybalance, is also important (105, 230).Although some improvement in FFM andin muscle strength can be achieved withnutritional intervention, particularlywhen coupled with an anabolic stimulus(229), nutritional interventions are notwidely used because of equivocal benefits(231). Well-designed randomizedcontrolled trials are needed to addressthis question.

A variety of anabolic drugs andbioactive nutrients have been tested withthe hope of improving muscle mass andstrength in COPD. None of them canbe recommended as routine treatment.Testosterone supplementation and itsanalogs are able to improve muscle strengthand mass (196, 232–236), but this does notnecessarily translate into improvedfunctional capacity. Also, the potential ofadverse events, including carcinogenesisand virilization, has limited the applicationof this intervention in clinical practice.Growth hormone and its analogs(237–241), megestrol acetate (242), creatine(243–246), L-carnitine (247), antioxidants(57, 248–250), and vitamin Dsupplementation (183, 251), alone or incombination with exercise training, havebeen tested in COPD. The role of thesetherapies is uncertain, and additionalstudies are warranted.

Suggestions for FutureResearch

Despite progressmade since the first ATS/ERSStatement on limb muscle in COPD, muchremains to be learned about this importantsystemic consequence. In the context ofa worldwide epidemic of obesity, the diagnosisof muscle atrophy may become more difficultas clinicians are likely to be misled bynormal or increased BMI, believing that thisimplies normal muscle mass. Althoughmuscle atrophy is less prevalent when BMI isnormal or increased, there is still anappreciable portion of patients who expressesmuscle atrophy and weakness (1).

There are some recommendations forfuture research:

1. If the question about presence of disuseversus specific COPD-related myopathy isto be answered, patients with COPDshould be matched with control subjectshaving a similar degree of physical activity,as assessed with activity monitors.

2. Widely accepted normative values forquadriceps muscle strength should bedetermined.

3. There is a need to know more about theonset of limb muscle dysfunction inCOPD. A focus on patientswith mild disease would be ofinterest. Longitudinal studies willbe important to understand whenthe muscle pathological processesstart and how they evolve over time.

4. Investigation of molecular mechanismsinvolved in initiation and developmentof limb muscle dysfunction is a key issue

Table 3: Effects of Treatments for Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Treatment Mass Strength Exercise Tolerance Survival

Exercise O (201) O (200, 201) O (265) ?Oxygen ? ? O (266–268) ONutrition alone No (269) No (269) No (269) ?Nutrition with exercise training O (228, 229, 270) O (229, 270) O (228, 229, 270) ?Nutrition with exercise training and anabolichormone supplementation

O (271) O (271) O (271) ?

Testosterone O (196) O (196) No (196, 233) ?Growth hormones O (240) No (240) No (240) ?Ghrelin ? ? ? ?Megestrol No (242) ? No (242) ?Creatine ? ? No (243, 244, 246) ?Antioxidants ? ? ? ?Vitamin D alone ? ? ? ?Vitamin D with exercise training ? ? ? ?

O: Studies support that the treatment has a favorable effect on the outcome; No: studies support that the treatment has no favorable effect on theoutcome; ?: there are no supporting data for a treatment effect on the outcome.



for development of specific and safetherapy for this problem.

5. Clinical trials are warranted to evaluateto which extent treatment of limbmuscle function affects clinicaloutcomes (exercise capacity, quality oflife, and survival) in COPD.

6. Large and multicenter studies inthoroughly phenotyped patients will beinstrumental in understanding specificrisk factors for developing limb muscledysfunction and evaluating treatmentfor this condition.

7. Whether muscle abnormalities can becompletely normalized with exercisetraining is a question that should beaddressed specifically in an adequatelypowered clinical trial.

8. In the context of increasingprevalence of (abdominal) obesity inCOPD, emphasis should be placedon possible biochemical cross-talkbetween fat and muscle. For example,it may be that limb muscledysfunction influences prevalence ofmetabolic syndrome.

Conclusions

Limb muscle dysfunction is a clinicallyrelevant systemic manifestation ofCOPD, because it influences importantclinical outcomes. This comorbidcondition can be treated with exercisetraining. Future research shouldallow a better understanding ofmechanisms involved in developmentof skeletal muscle dysfunction, with thehope for development of specifictherapies. n

This statement was prepared by an ad hoc subcommittee of the ATS Assembly on Pulmonary Rehabilitation and the ERS Scientific Group 01.02“Rehabilitation and Chronic Care.”

Members of this committee were as follows:

FRANCOIS MALTAIS, M.D. (Chair)MARC DECRAMER, PH.D., M.D. (Co-Chair)ESTHER BARREIRO, M.D., PH.D.YAN BURELLE, PH.D.RICHARD CASABURI, PH.D., M.D.RICHARD DEBIGARE, PH.D.P. N. RICHARD DEKHUIJZEN, M.D., PH.D.FRITS FRANSSEN, M.D., PH.D.GHISLAINE GAYAN-RAMIREZ, PH.D.JOAQUIM GEA, M.D.HARRY R. GOSKER, PH.D.RIK GOSSELINK, PH.D.MAURICE HAYOT, PH.D., M.D.SABAH N. A. HUSSAIN, PH.D., M.D.WIM JANSSENS, PH.D., M.D.MICHAEL I. POLKEY, PH.D.JOSEP ROCA, M.D.DIDIER SAEY, P.T., PH.D.ANNEMIE M. W. J. SCHOLS, PH.D.

MARTIJN A. SPRUIT, PH.D.MICHAEL STEINER, M.D.TANJA TAIVASSALO, PH.D.THIERRY TROOSTERS, PH.D.IOANNIS VOGIATZIS, PH.D.PETER D. WAGNER, M.D.

Author Disclosures: F.M. was on an advisorycommittee and received speaker fees fromGlaxoSmithKline ($5,000–24,999 combined); hereceived research support from GlaxoSmithKline($50,000–99,999). R.C. received researchsupport from Novartis ($100,000–249,999). J.G.holds a patent for a training valve, with proceedspaid to his institution. W.J. received speaker feesfrom AstraZeneca ($1–4,999), was on anadvisory committee and received speaker feesfrom Boehringer Ingelheim ($1–4,999combined), and received research supportfrom Boehringer Ingelheim ($5,000–24,999);

he was on an advisory committee of Chiesi($1–4,999), and on an advisory committeeand received speaker fees fromGlaxoSmithKline ($1–4,999 combined); hewas on an advisory committee and receivedspeaker fees from Novartis ($1–4,999combined). M.D., E.B., Y.B., R.D., P.N.R.D.,F.F., G.G-R., H.R.G., R.G., M.H., S.N.A.H.,M.I.P., J.R., D.S., A.M.W.J.S., M.A.S.,M.S., T. Taivassalo, T. Troosters., I.V., andP.D.W. reported no relevant commercialinterests.

Acknowledgment: The authors thankAnnette De Bruyne and Eline Lahousse fortheir secretarial assistance and Helene Trudel,for drawing the figures. They also thankKevin Wilson and Guy Brusselle for theirguidance during the preparation of thisdocument.

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