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Estrogen-related 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 mitigation of dystrophy in DMD is not known. We have investigated ERR\u03b1 signaling in pre-clinical 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 vitro 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 defect 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, and boosted regeneration after BaCl2 injury in dystrophic muscle. Our studies demonstrate a pro-regenerative role of ERR\u03b1 and its deficiency in dystrophic muscles and its MuSCs. ERR\u03b1 restoration could be a therapeutic strategy for DMD through angio-metabolic gene program.\n                <\/jats:p>","DOI":"10.1101\/2025.05.15.654390","type":"posted-content","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T12:20:13Z","timestamp":1747657213000},"source":"Crossref","is-referenced-by-count":1,"title":["Estrogen-related receptor alpha promotes skeletal muscle regeneration and mitigates muscular dystrophy"],"prefix":"10.64898","author":[{"given":"Thi Thu Hao","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya Xiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svitlana","family":"Poliakova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Citu","family":"Citu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eira","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danesh H.","family":"Sopariwala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-0914","authenticated-orcid":false,"given":"Zhongming","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-2848","authenticated-orcid":false,"given":"Ashok","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vihang A.","family":"Narkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025052119050668000_2025.05.15.654390v1.1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008342"},{"key":"2025052119050668000_2025.05.15.654390v1.2","unstructured":"Cheung, T.H. , Rando, T.A ., Molecular regulation of stem cell quiescence. 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