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Although transmembrane protein fibronectin type III domain protein 5 (FNDC5)\/Irisin is known to mediate the protective effects of exercise on ischemic heart, its effects and mechanisms on mitochondria after myocardial infarction are not fully defined. We randomized wild and\n                    <jats:italic>FNDC5<\/jats:italic>\n                    knockout (KO) mice on which to construct a post\u2010infarction exercise rehabilitation model, and subsequently compared the differences in cardiac and myocardial mitochondrial structure and function between groups; the FNDC5\/Irisin\u2010AMPK\u2010Sirt1 mitochondrial pathway was further assessed by applying recombinant human Irisin,\n                    <jats:italic>FNDC5<\/jats:italic>\n                    and\/or\n                    <jats:italic>Sirt1<\/jats:italic>\n                    knockdown (KD) treatment to neonatal mouse cardiomyocytes. Transmission electron microscopy was used to examine mitochondrial structure, Oxygraph\u20102k was used to measure mitochondrial function, and immunoblotting was used to assess mitochondrial genesis, mitophagy marker proteins, and pathway\u2010related proteins.\n                    <jats:italic>FNDC5<\/jats:italic>\n                    <jats:sup>KO<\/jats:sup>\n                    induced abnormalities of myocardial mitochondrial genesis and mitophagy, weakened the improvement effect of exercise toward mitochondrial injury and was associated with deteriorated cardiac function after myocardial infarction.\n                    <jats:italic>Sirt1<\/jats:italic>\n                    <jats:sup>KD<\/jats:sup>\n                    weakened the FNDC5\/Irisin\u2010mediated regulatory effect of exercise on mitochondrial genesis and mitophagy in primary cardiomyocytes. Exercise induced FNDC5\/Irisin is an important regulator of the ameliorative effects of Sirt1 on cardiac function and mitochondrial remodeling during infarction rehabilitation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500863rrrr","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T14:07:43Z","timestamp":1769695663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deficiency of\n                    <scp>FNDC5<\/scp>\n                    \/Irisin Impairs the Protective Effect of Exercise Against Post\u2010Infarction Myocardial Mitochondrial Injury"],"prefix":"10.1096","volume":"40","author":[{"given":"Shuguang","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University  Xi'an China"},{"name":"Institute of Sports and Exercise Biology, School of Physical Education Shaanxi Normal University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology, School of Physical Education Shaanxi Normal University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-2910","authenticated-orcid":false,"given":"Wujing","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology, School of Physical Education Shaanxi Normal University  Xi'an 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, School of Physical Education Shaanxi Normal University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangzhuo","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology, School of Physical Education Shaanxi Normal University  Xi'an China"},{"name":"School of Life Science and Technology Xi'an Jiaotong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Bo","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology, School of Physical Education Shaanxi Normal University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7911-6048","authenticated-orcid":false,"given":"Zhenjun","family":"Tian","sequence":"additional","affiliation":[{"name":"Institute of Sports and Exercise Biology, School of Physical Education Shaanxi Normal University  Xi'an 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