{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:53:28Z","timestamp":1788976408142,"version":"build-2803163510"},"reference-count":159,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII) and the European Union","award":["PI21\/00785"],"award-info":[{"award-number":["PI21\/00785"]}]},{"name":"Instituto de Salud Carlos III (ISCIII) and the European Union","award":["PI25\/01093"],"award-info":[{"award-number":["PI25\/01093"]}]},{"name":"SEPAR Research Grant 2025"},{"DOI":"10.13039\/100006301","name":"CIBER","doi-asserted-by":"crossref","award":["CB06\/0043"],"award-info":[{"award-number":["CB06\/0043"]}],"id":[{"id":"10.13039\/100006301","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Skeletal muscle dysfunction is a major systemic manifestation of COPD that shapes symptoms, exercise tolerance and mortality. Current evidence can be integrated within a Damage\u2013Regeneration\u2013Remodeling framework linking mechanics and biology to clinical phenotypes. Pulmonary hyperinflation and chest wall geometry chronically load the diaphragm and other respiratory muscles in COPD, whereas inactivity and exacerbation-related disuse underload locomotor muscles. Across muscle compartments, oxidative\/nitrosative stress, activation of proteolytic pathways, mitochondrial and endoplasmic reticulum stress, microvascular limitations, neuromuscular junction instability, and myosteatosis degrade muscle quality. The diaphragm adapts with a fast-to-slow fiber shift, greater oxidative capacity, and sarcomere foreshortening, improving endurance, whereas limb muscles show atrophy, a glycolytic shift, reduced oxidative enzymes, extracellular matrix accrual, and fat infiltration. Translational levers that address these mechanisms include: (I) Reduce damage: bronchodilation, lung-volume reduction, oxygen, non-invasive ventilation, early mobilization, pulmonary rehabilitation, neuromuscular stimulation, and corticosteroid stewardship; (II) Enable regeneration: progressive resistance plus high-intensity\/heavy-load endurance training; adequate protein and vitamin-D intake, and endocrine correction; and (III) Steer remodeling: increase physical activity (with\/without coaching\/telecoaching), functional assessment and CT or MRI monitoring, inspiratory-muscle training, and phenotype-guided adjuncts in selected cases. This framework clarifies why lung deflation strategies benefit inspiratory mechanics, whereas limb recovery requires behavioral and metabolic interventions layered onto systemic optimization.<\/jats:p>","DOI":"10.3390\/cells14211731","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T11:11:16Z","timestamp":1762254676000},"page":"1731","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Biological Mechanisms Involved in Muscle Dysfunction in COPD: An Integrative Damage\u2013Regeneration\u2013Remodeling Framework"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8718-7346","authenticated-orcid":false,"given":"Joaquim","family":"Gea","sequence":"first","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"},{"name":"MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3209-3462","authenticated-orcid":false,"given":"Mauricio","family":"Orozco-Levi","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"},{"name":"Respiratory Medicine Department, Fundaci\u00f3n Cardiovascular de Colombia (FCV), Hospital Internacional de Colombia (HIC), Universidad de Santander (UDES), Floridablanca 681004, Santander, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6567-0916","authenticated-orcid":false,"given":"Sergi","family":"Pascual-Gu\u00e0rdia","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6458-8972","authenticated-orcid":false,"given":"Carme","family":"Casadevall","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"},{"name":"MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5944-6555","authenticated-orcid":false,"given":"C\u00e9sar Jess\u00e9","family":"Enr\u00edquez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"},{"name":"MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7953-8455","authenticated-orcid":false,"given":"Ramon","family":"Camps-Ubach","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2708-3443","authenticated-orcid":false,"given":"Esther","family":"Barreiro","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Department, Hospital del Mar Research Institute, \u00c1rea de Enfermedades Respiratorias, CIBER, ISCIII, 08003 Barcelona, Spain"},{"name":"MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"ref_1","unstructured":"(2025, October 27). 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