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However, the source of endogenous ELA and its molecular mechanism in myocardial fibrosis inhibition remain incompletely understood. Herein, we found that aerobic exercise significantly improved renal apoptosis caused by MI, inhibited inflammation, attenuated structural damage, enhanced renal function, and increased expression and secretion levels of renal ELA. Aerobic exercise stimulated the circulation of renal\u2010derived ELA to reach the MI heart and played a protective role. Under aerobic exercise intervention, renal\u2010specific\n                    <jats:italic>Elabela<\/jats:italic>\n                    overexpression improved myocardial pathological remodeling, decreased cardiomyocyte apoptosis, and enhanced cardiac function. Renal\u2010specific\n                    <jats:italic>Elabela<\/jats:italic>\n                    knockdown significantly increased cardiac apoptosis, inflammation, and fibrosis levels in MI mice, leading to severe impairment of cardiac function. Following AMPK agonist intervention, ELA expression in HKC cells and culture medium increased in a concentration\u2010dependent manner. ELA\u201014 significantly activated the APJ\u2010AMPK\u2010Sirt1 signaling pathway and inhibited\n                    <jats:italic>Tgf\u2010\u03b21<\/jats:italic>\n                    transcription by regulating Sirt1 translocation, and AMPK inhibitor weakened ELA\u201014 function. In cultured cardiac fibroblasts (CFs), the intervention of ELA\u201014 significantly inhibited the activity of the TGF\u03b21\u2010Smad2\/3 signaling pathway, downregulated the expression of fibrosis\u2010related proteins, increased apoptosis, and lowered the cell migration rate. After TGF\u03b2R1 inhibitor intervention, ELA\u201014 showed a loss of regulation of CFs. Aerobic exercise stimulates the expression of renal\u2010derived ELA, which reaches the MI heart through blood circulation. Renal\u2010derived ELA partly exerts its antifibrotic effects by activating the APJ\u2010AMPK\u2010Sirt1 pathway and inhibiting the TGF\u03b21\u2010Smad2\/3 signaling pathway, contributing to its cardiac protective effects.\n                  <\/jats:p>","DOI":"10.1096\/fj.202402897rr","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T11:31:40Z","timestamp":1750419100000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Aerobic Exercise Upregulates Renal\u2010Derived ELABELA to Improve Myocardial Fibrosis by Activating APJ\u2010AMPK\u2010Sirt1 and Inhibiting TGF\u03b21\u2010Smad2\/3 Signaling Pathways in Myocardial Infarction Mice"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-2910","authenticated-orcid":false,"given":"Wujing","family":"Ren","sequence":"first","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2789-7674","authenticated-orcid":false,"given":"Yue","family":"Xi","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of China"},{"name":"Division of Endocrinology, Diabetes and Nutrition, Department of Medicine University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Duan","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianmu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuguang","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da\u2010Wei","family":"Gong","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Nutrition, Department of Medicine University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8747-6161","authenticated-orcid":false,"given":"Zhenjun","family":"Tian","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology Shaanxi Normal University  Xi'an Shaanxi People's Republic of 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