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The gene is prone to mutations that cause a loss of protein function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>BRCA1\/Brca1 has recently been found to regulate several cellular pathways beyond DNA repair and is expressed in skeletal muscle.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Skeletal muscle specific knockout of <jats:italic>Brca1<\/jats:italic> in mice caused a loss of muscle quality, identifiable by reductions in muscle force production and mitochondrial respiratory capacity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Loss of muscle quality was associated with a shift in muscle phenotype and an accumulation of mitochondrial DNA mutations.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results demonstrate that BRCA1 is necessary for skeletal muscle function and that increased mitochondrial DNA mutations may represent a potential underlying mechanism.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Recent evidence suggests that the breast cancer 1 early onset gene (<jats:italic>BRCA1<\/jats:italic>) influences numerous peripheral tissues, including skeletal muscle. The present study aimed to determine whether induced\u2010loss of the breast cancer type 1 susceptibility protein (Brca1) alters skeletal muscle function. We induced genetic ablation of exon 11 in the <jats:italic>Brca1<\/jats:italic> gene specifically in the skeletal muscle of adult mice to generate skeletal muscle\u2010specific <jats:italic>Brca1<\/jats:italic> homozygote knockout (Brca1KO<jats:sup>smi<\/jats:sup>) mice. Brca1KO<jats:sup>smi<\/jats:sup> exhibited kyphosis and decreased maximal isometric force in limb muscles compared to age\u2010matched wild\u2010type mice. Brca1KO<jats:sup>smi<\/jats:sup> skeletal muscle shifted toward an oxidative muscle fibre type and, in parallel, increased myofibre size and reduced capillary numbers. Unexpectedly, myofibre bundle mitochondrial respiration was reduced, whereas contraction\u2010induced lactate production was elevated in Brca1KO<jats:sup>smi<\/jats:sup> muscle. Brca1KO<jats:sup>smi<\/jats:sup> mice accumulated mitochondrial DNA mutations and exhibited an altered mitochondrial morphology characterized by distorted and enlarged mitochondria, and these were more susceptible to swelling. In summary, skeletal muscle\u2010specific loss of Brca1 leads to a myopathy and mitochondriopathy characterized by reductions in skeletal muscle quality and a consequent kyphosis. Given the substantial impact of <jats:italic>BRCA1<\/jats:italic> mutations on cancer development risk in humans, a parallel loss of BRCA1 function in patient skeletal muscle cells would potentially result in implications for human health.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276863","type":"journal-article","created":{"date-parts":[[2018,12,17]],"date-time":"2018-12-17T03:39:41Z","timestamp":1545017981000},"page":"869-887","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Induced <i>in vivo<\/i> knockdown of the <i>Brca1<\/i> gene in skeletal muscle results in skeletal muscle weakness"],"prefix":"10.1113","volume":"597","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0466-6462","authenticated-orcid":false,"given":"Michael D.","family":"Tarpey","sequence":"first","affiliation":[{"name":"Department of Physiology Brody School of Medicine East Carolina University  Greenville NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P.","family":"Valencia","sequence":"additional","affiliation":[{"name":"School of Public Health Department of Kinesiology University of Maryland  College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn C.","family":"Jackson","sequence":"additional","affiliation":[{"name":"School of Public Health Department of Kinesiology University of Maryland  College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Amorese","sequence":"additional","affiliation":[{"name":"Department of Physiology Brody School of Medicine East Carolina University  Greenville NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P.","family":"Balestrieri","sequence":"additional","affiliation":[{"name":"Department of Physiology Brody School of Medicine East Carolina University  Greenville NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall H.","family":"Renegar","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Brody School of Medicine at East Carolina University  Greenville NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J. 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