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Estrogen\u2010related receptor alpha (ERR\u03b1) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERR\u03b1 activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERR\u03b1 signaling in pre\u2010clinical models of acute muscle injury and DMD. ERR\u03b1 is induced in differentiating C2C12 myoblast and regenerating muscle. ERR\u03b1 silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERR\u03b1 knockdown in proliferating cells, whereas oxidative mitochondrial and differentiation regulator genes were downregulated in differentiating cells. In accordance with in\u00a0vitro findings, transgenic ERR\u03b1 overexpression in rodent skeletal muscle stimulates muscle regeneration after acute BaCl\n                    <jats:sub>2<\/jats:sub>\n                    injury, which is accompanied by enhanced angiogenesis and mitochondrial biogenesis. Notably, ERR\u03b1 and its angiogenic and metabolic target gene expression is suppressed in muscle stem cells (MuSCs) derived from dystrophic muscles in mdx mice, coinciding with proliferation and differentiation defects in these cells. Loss of ERR\u03b1 and its target gene expression was recapitulated in adult dystrophic mdx muscles. Consequently, muscle specific ERR\u03b1 overexpression in mdx mice restored angiogenic and metabolic gene expression, induced vascular and oxidative remodeling, alleviated baseline muscle damage, boosted regeneration in dystrophic muscle and improved function. Our studies demonstrate a pro\u2010regenerative role of ERR\u03b1 and its deficiency in dystrophic muscles and MuSCs. ERR\u03b1 activation could be a therapeutic strategy for DMD through angio\u2010metabolic gene programming.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501764r","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T14:40:04Z","timestamp":1760020804000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Estrogen\u2010Related Receptor Alpha Promotes Skeletal Muscle Regeneration and Mitigates Muscular Dystrophy"],"prefix":"10.1096","volume":"39","author":[{"given":"Thi Thu Hao","family":"Nguyen","sequence":"first","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School UTHealth  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya Xiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School UTHealth  Houston Texas 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-083X","authenticated-orcid":false,"given":"Vihang A.","family":"Narkar","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School UTHealth  Houston Texas USA"},{"name":"The Unviersity of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008342"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3591"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-48156-7"},{"key":"e_1_2_8_5_1","first-page":"69","article-title":"Impaired Regeneration in Dystrophic Muscle\u2010New Target for Therapy","volume":"13","author":"Yanay 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