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To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15\u2010day\u2010old smKO mice, and myopathy symptoms could be detected by 2\u00a0months of age, worsening over time. rAAV9\u2010Ndufs3 delivered systemically into 15\u2010 to 18\u2010day\u2010old mice effectively restored NDUFS3 levels in skeletal muscle, precluding the development of the myopathy. To test the ability of rAAV9\u2010mediated gene replacement to revert muscle function after disease onset, we also treated post\u2010symptomatic, 2\u2010month\u2010old mice. The injected mice showed a remarkable improvement of the mitochondrial myopathy and biochemical parameters, which remained for the duration of the study. Our results showed that muscle pathology could be reversed after restoring complex I, which was absent for more than 2\u00a0months. These findings have far\u2010reaching implications for the ability of muscle to tolerate a mitochondrial defect and for the treatment of mitochondrial myopathies.<\/jats:p>","DOI":"10.15252\/emmm.201910674","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T08:56:13Z","timestamp":1578560173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Myopathy reversion in mice after restauration of mitochondrial complex I"],"prefix":"10.1038","volume":"12","author":[{"given":"Claudia V","family":"Pereira","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Peralta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Arguello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra R","family":"Bacman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisca","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8077-7092","authenticated-orcid":false,"given":"Carlos T","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"BFEMMM201910674_CR1","doi-asserted-by":"crossref","first-page":"43081","DOI":"10.1074\/jbc.M304998200","volume":"278","author":"H Antonicka","year":"2003","unstructured":"Antonicka H, Ogilvie I, Taivassalo T, Anitori RP, Haller RG, Vissing J, Kennaway NG, Shoubridge EA (2003) Identification and characterization of a common set of complex I assembly intermediates in mitochondria from patients with complex I deficiency. 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