HIGHLIGHTED TOPIC | Muscle Dysfunction in COPDMuscle Dysfunction in COPDMuscle dysfunction in COPDEsther Barreiro, and Gary SieckEsther BarreiroRespiratory Medicine Department—Lung Cancer Research Group, Institute of Medical Research of Hospital del Mar (IMIM)-Hospital del Mar, Parc de Salut Mar, Barcelona Biomedical Research Park (PRBB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Bunyola, Majorca, Balearic Islands, Spain; and , and Gary SieckDepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MinnesotaPublished Online:01 May 2013https://doi.org/10.1152/japplphysiol.00162.2013This is the final version - click for previous versionMoreSectionsPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations chronic obstructive pulmonary disease (COPD) is a highly prevalent condition that is projected to be the third leading cause of death worldwide in 2020. COPD imposes a significant economic burden in different countries as a consequence of acute exacerbations and comorbidities. In patients with COPD, skeletal muscle dysfunction is a common systemic manifestation that affects both respiratory and limb muscles and has a significant impact on exercise tolerance and quality of life (8). As a matter of fact, quadriceps muscle dysfunction, mainly characterized by reduced muscle force, is observed in one-third of all patients with COPD, even at very early stages of their disease (17). In addition, quadriceps weakness and reduced muscle mass are reliable predictors of COPD mortality (13, 18).Although it has been well characterized that COPD muscle dysfunction is the result of the complex interaction between systemic and local factors, the etiology of muscle dysfunction remains to be fully identified. Interestingly, although hyperinflation and an increased work of breathing appear to be the main contributing events to respiratory muscle dysfunction, deconditioning seems to play a major role in the dysfunction of peripheral muscles in COPD. Other factors such as cigarette smoke, nutritional abnormalities, exacerbations, drugs, hypoxia, hypercapnia, comorbidities, and physical activity also influence muscle mass and function in patients with COPD (1–3, 5, 11, 18). In addition, derangements of key molecular and cellular processes such as redox imbalance, mitochondrial dysfunction, enhanced protein catabolism and reduced protein anabolism, structural alterations, and systemic inflammation also modify muscle phenotype and function in patients with COPD.In the current Highlighted Topic on “Muscle Dysfunction in COPD,” renowned investigators in the field explore the most relevant mechanisms that participate in the pathophysiology of skeletal muscle dysfunction of patients with COPD. These authors from around the world review and assess the most up-to-date literature on specific topics such as motor control abnormalities (12), remodeling (10), cachexia (15), epigenetics (4), autophagy (9), and metabolic alterations including mitochondrial dysfunction (14) taking place in both respiratory and limb muscles of patients with COPD. Furthermore, the influence of exacerbations (6) and exercise training (16) on muscle mass maintenance and performance has also been described in two additional mini-reviews of this highlighted topic. A brief summary of the different aspects addressed in each of the mini-reviews is provided below.In the first review of this series, Gea et al. (7) provide a general overview of the main molecular and cellular alterations encountered within the muscle fibers of patients with COPD and how these changes may account for the muscle contractile dysfunction and mass loss observed in COPD.Mantilla and Sieck (12) examine to what extent alterations in different motor unit (muscle fiber) types contribute to muscle dysfunction in COPD. Moreover, they examine the potential factors and mechanisms that may impair the neuromotor control of respiratory and limb muscles and how these alterations impair muscle performance in patients with COPD.Levine et al. (10) explore the mechanisms thought to mediate the differential remodeling features observed in the diaphragm and vastus lateralis muscles of patients with COPD. Additionally, the pathophysiology of muscle remodeling is reviewed.Remels et al. (15) analyze the pathophysiological mechanisms involved in muscle wasting and weakness in patients with COPD. Oxidative stress, systemic inflammation, and myostatin seem to be potent inducers of muscle mass loss and wasting in COPD.Barreiro et al. (4) review the potential implications of epigenetic mechanisms in the regulation of muscle mass maintenance and differentiation in muscles of patients with COPD. In addition, they provide an extensive review of the specific actions and processes by which epigenetic mechanisms control embryonic myogenesis, muscle proliferation, and differentiation.Hussain et al. (9) assess recent progress involving the molecular structure and function of the autophagy-lysosome pathway within skeletal muscles in health and disease. Autophagy seems to be crucial in the regulation of muscle mass maintenance and performance. Preliminary results point toward an induction of the autophagy-lysosome pathway in peripheral muscles of patients with COPD.Puente-Maestu et al. (14) evaluate the potential implications of mitochondrial dysfunction in both respiratory and limb muscles of patients with COPD. Mitochondrial alterations in muscles of these patients are mainly characterized by a reduction in oxidative capacity and enhanced production of reactive oxidants. Moreover, the characteristic phenotype observed in the vastus lateralis of patients with severe COPD, which renders the muscle less fatigue resistant, seems to correlate with a decrease in the number of mitochondria but an increased production of reactive oxidants within the mitochondria.Gayan-Ramirez et al. (6) describe the pathophysiological mechanisms leading to enhanced catabolism in muscles of patients with COPD during exacerbations. The relevance of these exacerbations lies in the fact that they increase the prevalence and severity of skeletal muscle dysfunction in patients with COPD. Therefore, exacerbations have a major impact on the quality of life of these patients. The authors argue that early measures should be taken (e.g., pulmonary rehabilitation) to prevent the deleterious effects on muscle biology and function during the course of exacerbations in patients with COPD.Ribeiro et al. (16) examine the different strategies and indications of pulmonary rehabilitation, including exercise training in patients with COPD. Furthermore, the specific beneficial effects in terms of muscle biology and physiology are also explored in their mini-review. Finally, these authors evaluate whether exercise training could have deleterious consequences in certain phenotypes of patients with COPD and/or clinical settings.In conclusion, we hope that the mini-reviews contained in the present highlighted topic encourage research in this specific arena with the aim of enhancing current knowledge on the pathophysiology of COPD muscle dysfunction. The ultimate goal should be to better treat and cure our patients by means of novel therapeutic strategies targeted to specific key physiological and cellular processes taking place in the muscles of such patients.GRANTSThis study has been supported by CIBERES, FIS 11/02029, FIS 12/02534, 2009-SGR-393, SEPAR 2010, FUCAP 2011, FUCAP 2012, and Marató TV3 (MTV3-07-1010) (Spain).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSAuthor contributions: E.B. and G.C.S. drafted manuscript; E.B. and G.C.S. edited and revised manuscript; E.B. and G.C.S. approved final version of manuscript.REFERENCES1. Barreiro E , de la PB , Minguella J , Corominas JM , Serrano S , Hussain SN , Gea J. Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 171: 1116–1124, 2005.Crossref | PubMed | ISI | Google Scholar2. Barreiro E , Peinado VI , Galdiz JB , Ferrer E , Marin-Corral J , Sanchez F , Gea J , Barbera JA. Cigarette smoke-induced oxidative stress: a role in chronic obstructive pulmonary disease skeletal muscle dysfunction. Am J Respir Crit Care Med 182: 477–488, 2010.Crossref | PubMed | ISI | Google Scholar3. Barreiro E , Schols AM , Polkey MI , Galdiz JB , Gosker HR , Swallow EB , Coronell C , Gea J. Cytokine profile in quadriceps muscles of patients with severe COPD. Thorax 63: 100–107, 2008.Crossref | PubMed | ISI | Google Scholar4. Barreiro E , Sznajder JI. Epigenetic regulation of muscle phenotype and adaptation: a potential role in COPD muscle dysfunction. J Appl Physiol; doi:10.1152/japplphysiol.01027.2012.ISI | Google Scholar5. Fermoselle C , Rabinovich R , Ausin P , Puig-Vilanova E , Coronell C , Sanchez F , Roca J , Gea J , Barreiro E. Does oxidative stress modulate limb muscle atrophy in severe COPD patients? Eur Respir J 40: 851–862, 2012.Crossref | PubMed | ISI | Google Scholar6. Gayan-Ramirez G , Decramer M. Mechanisms of striated muscle dysfunction during acute exacerbations of COPD. J Appl Physiol; doi:10.1152/japplphysiol.00847.2012.ISI | Google Scholar7. Gea J , Agusti A , Roca J. Pathophysiology of muscle dysfunction in COPD. J Appl Physiol; doi:10.1152/japplphysiol.00981.2012.ISI | Google Scholar8. Gosselink R , Troosters T , Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 153: 976–980, 1996.Crossref | PubMed | ISI | Google Scholar9. Hussain SN , Sandri M. Role of autophagy in COPD skeletal muscle dysfunction. J Appl Physiol; doi:10.1152/japplphysiol.00893.2012.ISI | Google Scholar10. Levine S , Bashir MH , Clanton TL , Powers SK , Singhal S. COPD elicits remodeling of the diaphragm and vastus lateralis muscles in humans. J Appl Physiol; 10.1152/japplphysiol.01121.2012.ISI | Google Scholar11. Maltais F , LeBlanc P , Jobin J , Berube C , Bruneau J , Carrier L , Breton MJ , Falardeau G , Belleau R. Intensity of training and physiologic adaptation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 155: 555–561, 1997.Crossref | ISI | Google Scholar12. Mantilla CB , Sieck GC. Neuromotor control in chronic obstructive pulmonary disease. J Appl Physiol; doi:10.1152/japplphysiol.01212.2012.ISI | Google Scholar13. Marquis K , Debigare R , Lacasse Y , LeBlanc P , Jobin J , Carrier G , Maltais F. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166: 809–813, 2002.Crossref | PubMed | ISI | Google Scholar14. Puente-Maestu L , Lazaro A , Humanes B. Metabolic derangements in COPD muscle dysfunction. J Appl Physiol; doi:10.1152/japplphysiol.00815.2012.ISI | Google Scholar15. Remels AH , Gosker HR , Langen RC , Schols AM. The mechanisms of cachexia underlying muscle dysfunction in COPD. J Appl Physiol; doi:10.1152/japplphysiol.00790.2012.ISI | Google Scholar16. Ribeiro F , Thériault ME , Debigaré R , Maltais F. Should all patients with COPD be trained? J Appl Physiol; doi:10.1152/japplphysiol.01124.2012.ISI | Google Scholar17. Seymour JM , Spruit MA , Hopkinson NS , Natanek SA , Man WD , Jackson A , Gosker HR , Schols AM , Moxham J , Polkey MI , Wouters EF. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 36: 81–88, 2010.Crossref | PubMed | ISI | Google Scholar18. Swallow EB , Reyes D , Hopkinson NS , Man WD , Porcher R , Cetti EJ , Moore AJ , Moxham J , Polkey MI. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 62: 115–120, 2007.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: E. Barreiro, IMIM-Hospital del Mar, UPF PRBB, C/Dr. Aiguader, 88, Barcelona, E-08003, Spain (e-mail: [email protected]es). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation CollectionsJAPPL CollectionsMuscle Dysfunction in COPD Cited ByInfluence of dietary nitrate supplementation on lung function and exercise gas exchange in COPD patientsNitric Oxide, Vol. 76Molecular and biological pathways of skeletal muscle dysfunction in chronic obstructive pulmonary disease23 June 2016 | Chronic Respiratory Disease, Vol. 13, No. 3A double blind randomized placebo control crossover trial on the effect of dietary nitrate supplementation on exercise tolerance in stable moderate chronic obstructive pulmonary disease2 May 2015 | BMC Pulmonary Medicine, Vol. 15, No. 1Respiratory and Limb Muscle Dysfunction in COPD1 December 2014 | COPD: Journal of Chronic Obstructive Pulmonary Disease, Vol. 12, No. 4High CO2 Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)Journal of Biological Chemistry, Vol. 290, No. 14Moving Towards Patient-Centered Medicine for COPD Management: Multidimensional Approaches versus Phenotype-Based Medicine—A Critical View10 June 2014 | COPD: Journal of Chronic Obstructive Pulmonary Disease, Vol. 11, No. 5Fiber atrophy, oxidative stress, and oxidative fiber reduction are the attributes of different phenotypes in chronic obstructive pulmonary disease patientsFares Gouzi, Aldjia Abdellaoui, Nicolas Molinari, Edith Pinot, Bronia Ayoub, Dalila Laoudj-Chenivesse, Jean-Paul Cristol, Jacques Mercier, Maurice Hayot, and Christian Préfaut15 December 2013 | Journal of Applied Physiology, Vol. 115, No. 12Common mechanisms of compensatory respiratory plasticity in spinal neurological disordersRespiratory Physiology & Neurobiology, Vol. 189, No. 2 More from this issue > Volume 114Issue 9May 2013Pages 1220-1221 Copyright & PermissionsCopyright © 2013 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00162.2013PubMed23393064History Published online 1 May 2013 Published in print 1 May 2013 Metrics