{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:58:15Z","timestamp":1791845895175,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400050"],"award-info":[{"award-number":["82400050"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Skeletal muscle dysfunction (SMD) is a common extrapulmonary complication of chronic obstructive pulmonary disease (COPD). Histone deacetylase 2 (HDAC2) is closely involved in the suppression of inflammatory transcription and is progressively reduced during COPD progression. Exosomes mediate intercellular communication by transferring bioactive cargos, including proteins. This study aimed to elucidate the molecular mechanism by which alveolar epithelial cell\u2010derived exosomes regulate HDAC2 and contribute to COPD\u2010related SMD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Exosome inhibitor GW4869 was used to assess the role of exosomes in skeletal muscle injury induced by chronic cigarette smoke (CS) exposure. Exosomes isolated from the bronchoalveolar lavage fluid (BALF) of CS\u2010exposed mice and from cigarette smoke extract (CSE)\u2010exposed mouse alveolar epithelial (MLE12) cells were applied to recipient mice and\/or mouse myoblast (C2C12) cells to evaluate muscle phenotypes, myogenic differentiation and cellular senescence. Rescue experiments using HDAC2 overexpression or HDAC activator ITSA1 treatment, together with proteomics and protein interaction assays, were performed to elucidate the underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GW4869 treatment ameliorated CS\u2010induced muscle dysfunction in mice, as evidenced by increased grip strength (222.4\u2009\u00b1\u200915.91\u2009g vs. 159.2\u2009\u00b1\u200911.65\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and muscle fibre cross\u2010sectional area (404.0\u2009\u00b1\u20095.15\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      vs. 172.0\u2009\u00b1\u20095.39\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), along with decreased muscle atrophy and senescence markers. In\u00a0vitro, exosomes derived from 8% CSE\u2010exposed MLE12 cells (Exo\u2010CSE) impaired myogenic differentiation, decreased myotube diameter (10.50\u2009\u00b1\u20090.74\u2009\u03bcm vs. 29.27\u2009\u00b1\u20090.48\u2009\u03bcm,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and increased the number of senescent cells (206.7\u2009\u00b1\u20095.13 vs. 9.33\u2009\u00b1\u20091.53,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Exo\u2010CSE significantly reduced HDAC2 expression in C2C12 cells (0.18\u2009\u00b1\u20090.03 vs. 0.53\u2009\u00b1\u20090.04,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), whereas HDAC2 overexpression or ITSA1 treatment rescued impaired myogenic differentiation and cellular senescence caused by Exo\u2010CSE. Proteomic analysis identified proline\/arginine\u2010rich end leucine\u2010rich protein (PRELP) as a key exosomal cargo, and exosomes derived from PRELP\u2010silenced CSE\u2010exposed MLE12 cells markedly restored HDAC2 expression in recipient C2C12 cells (0.42\u2009\u00b1\u20090.02 vs. 0.18\u2009\u00b1\u20090.03,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Mechanistically, PRELP disrupted the stabilizing interaction between heat shock protein family A member 5 (HSPA5) and HDAC2, accelerating HDAC2 degradation, likely through the ubiquitin\u2010proteasome pathway. In\u00a0vivo, the combination of PRELP knockdown and the HDAC activator ITSA1 synergistically alleviated CS\u2010induced muscle atrophy and senescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In COPD, CS\u2010exposed alveolar epithelial cells release PRELP\u2010enriched exosomes that promote SMD by disrupting HSPA5\u2010mediated HDAC2 stabilization and accelerating HDAC2 degradation. Targeting the PRELP\u2010HDAC2 axis may represent a potential therapeutic strategy for COPD\u2010related SMD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70349","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:30:23Z","timestamp":1784521823000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cigarette Smoke\u2010Exposed Alveolar Epithelial Cell\u2010Derived Exosomes Exacerbate Skeletal Muscle Dysfunction Through HDAC2 Signalling"],"prefix":"10.1002","volume":"17","author":[{"given":"Chao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine Hunan Provincial People's Hospital and the First\u2010Affiliated Hospital of Hunan Normal University  Changsha China"},{"name":"Clinical Medicine Research Center for Respiratory Rehabilitation in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MingZhi","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Changsha Hospital for Maternal and Child Health Care  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Hunan Provincial People's Hospital and the First\u2010Affiliated Hospital of Hunan Normal University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuiXian","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine The First Affiliated Hospital of Guangxi Medical University  Nanning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YongLiang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Hunan Provincial People's Hospital and the First\u2010Affiliated Hospital of Hunan Normal University  Changsha China"},{"name":"Clinical Medicine Research Center for Respiratory Rehabilitation in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S4480"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/resp.13416"},{"key":"e_1_2_10_4_1","first-page":"3291","article-title":"Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease","volume":"16","author":"Song Y.","year":"2024","journal-title":"Aging and 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