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We hypothesised that sarcopenia defines a specific clinical phenotype in COPD irrespective of respiratory disease severity. Markers of myostatin\/Smad2\/Smad3 and IGF-1\/PI3K\/Akt may be differentially expressed in the vastus lateralis (VL) of patients with COPD-associated sarcopenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In muscle specimens from VL, markers of the myostatin\/Smad2\/Smad3, Smad4 and IGF-1\/PI3K\/Akt pathways were evaluated (real-time PCR and immunoblotting) and correlations between clinical and biological variables of patients with sarcopenia (n=23), without sarcopenia (n=18) and healthy controls (n=13) were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the VL of sarcopenic COPD patients, expression levels of myostatin, Smad2\/Smad3 and Smad4 increased compared with those in nonsarcopenic patients and healthy controls. In sarcopenic limb muscles of patients with COPD, the myostatin Smad2\/Smad3 pathway was differentially activated from patients without sarcopenia and healthy controls. Among sarcopenic patients, myostatin and p-Smad3\/Smad3 levels negatively correlated with fat-free mass index (r=\u22120.727, p=0.026 and r=\u22120.703, p=0.035, respectively), myostatin and Smad4 levels correlated with quadriceps strength (r=\u22120.886, p=0.003 and r=\u22120.431, p=0.040, respectively) and myostatin correlated with diffusion capacity (r=\u22120.781, p=0.022). Remarkable negative correlations were observed between clinical parameters related to body composition and quadriceps muscle strength and levels of the myostatin Smad2\/Smad3 pathway, suggesting its implication in the process of muscle atrophy in COPD. IGF1 gene expression was also upregulated in the VL of sarcopenic patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, these findings offer a potential therapeutic target in COPD-associated sarcopenia.<\/jats:p><\/jats:sec>","DOI":"10.1183\/23120541.00772-2024","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T04:01:55Z","timestamp":1734062515000},"page":"00772-2024","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Myostatin\/Smad2\/Smad3 pathway define a differential clinical phenotype in COPD-associated sarcopenia"],"prefix":"10.1183","volume":"11","author":[{"given":"Adriana","family":"N\u00fa\u00f1ez-Robainas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Guitart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e1n","family":"L\u00f3pez-Postigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Sancho-Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2708-3443","authenticated-orcid":false,"given":"Esther","family":"Barreiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"key":"2025042204401118000_11.2.00772-2024.1","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afac169"},{"key":"2025042204401118000_11.2.00772-2024.2","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afy169"},{"key":"2025042204401118000_11.2.00772-2024.3","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.807583"},{"key":"2025042204401118000_11.2.00772-2024.4","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/jcsm.12600","article-title":"Diagnosis, prevalence, and clinical impact of sarcopenia in COPD: a systematic review and meta-analysis","volume":"11","author":"Sep\u00falveda-Loyola","year":"2020","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"2025042204401118000_11.2.00772-2024.5","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2006.062026"},{"key":"2025042204401118000_11.2.00772-2024.6","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1164\/rccm.201412-2189OE","article-title":"Muscle dysfunction in patients with lung diseases a growing epidemic","volume":"191","author":"Barreiro","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"2025042204401118000_11.2.00772-2024.7","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201710-2140CI"},{"key":"2025042204401118000_11.2.00772-2024.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamda.2016.06.001"},{"key":"2025042204401118000_11.2.00772-2024.9","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afy169"},{"key":"2025042204401118000_11.2.00772-2024.10","doi-asserted-by":"publisher","DOI":"10.1177\/1479972316642366"},{"key":"2025042204401118000_11.2.00772-2024.11","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.3390\/nu12082401","article-title":". 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