{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:02:12Z","timestamp":1791396132581,"version":"4.3.3"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"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":["82371639"],"award-info":[{"award-number":["82371639"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301828"],"award-info":[{"award-number":["82301828"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971364"],"award-info":[{"award-number":["81971364"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2021YFC2701300"],"award-info":[{"award-number":["2021YFC2701300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2021YFC2701302"],"award-info":[{"award-number":["2021YFC2701302"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2022CFB124"],"award-info":[{"award-number":["2022CFB124"]}],"id":[{"id":"10.13039\/501100003819","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":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Few researches have investigated the molecular mechanism responsible for the age\u2010related loss of the pelvic floor muscle (PFM) mass and functionality\u2014a pivotal contributor to pelvic organ prolapse and diminished physical well\u2010being. ADP ribosylation factor GTPase activating protein 3 (ArfGAP3) is a member of ArfGAPs, which regulates the vesicular trafficking pathway and intracellular proteins transporting. However, its effects on skeletal muscle ageing remain largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mouse models of natural ageing and D\u2010gal (D\u2010galactose)\u2013induced ageing were subject to analyse the structure, function and pathological alterations of the PFM and the expression of ArfGAP3. Stable ArfGAP3 knockdown and overexpression C2C12 cell lines were established to investigate the anti\u2010senescence effects of ArfGAP3 and the underlying mechanisms in ageing process, complemented by Rab5a genetic intervention and mRFP\u2010GFP\u2010LC3 adenoviral particles transfection. In\u00a0vivo experiments entailed ArfGAP3 overexpression in mice alongside autophagy inhibitor treatment, with assessments encompassing tissue mass, bladder leak point pressure (BLPP), submicroscopic structure, antioxidative stress system and muscle regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Aged (24\u2010month\u2010old) mice exhibited significant physiological alterations in PFMs, including decreased muscle mass, diminished cross\u2010sectional area (CSA), deteriorated supporting function (as evidenced by reduced BLPP), impaired autophagy and increased levels of oxidative stress (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Utilizing ageing C2C12 model, we observed a dose\u2010dependent relationship between D\u2010gal induction and cellular senescence, impaired differentiation and mitochondrial damage. Remarkably, the expression levels of ArfGAP3 were markedly downregulated in both in\u00a0vitro and in\u00a0vivo ageing models. Knockdown of ArfGAP3 exacerbated impaired differentiation potential and induced aberrant mitochondrial morphology and functional dysfunction in ageing C2C12 myoblasts, whereas ArfGAP3 overexpression largely mitigated these effects. Mechanistically, our findings revealed an interplay between ArfGAP3 and Rab5a, indicating their coordinated regulation. ArfGAP3\u2010mediated activation of Rab5a\u2010associated autophagy and IRS1\u2010AKT\u2010mTOR signalling pathways during cellular senescence and myogenesis was identified, leading to enhanced autophagic flux and improved resistance to oxidative stress. In\u00a0vivo, ArfGAP3 overexpression ameliorated D\u2010gal\u2013induced loss of muscle mass and function, while promoting antioxidant responses and muscle regeneration in mice. However, these protective effects of ArfGAP3 overexpression were extinguished by autophagy inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study uncovers the significant role of ArfGAP3 in enhancing differentiation capacity and mitochondrial function through mediating Rab5a expression to activate IRS1\u2010AKT\u2010mTOR signalling pathways and promote autophagy during the ageing process. These findings underscore the potential of ArfGAP3 as a promising therapeutic target for ameliorating the decline in skeletal muscle function associated with ageing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13725","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T19:11:51Z","timestamp":1739819511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["ArfGAP3 Protects Mitochondrial Function and Promotes Autophagy Through Rab5a\u2010Mediated Signals in Ageing Skeletal Muscle"],"prefix":"10.1002","volume":"16","author":[{"given":"Mao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics Renmin Hospital of Wuhan University  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Pelvic Floor Disease  Wuhan Hubei 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