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However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mitochondrial respiration, enzyme activity, and gene expression were examined in <jats:italic>pectoralis major<\/jats:italic> biopsies from age\u2010matched male (<jats:italic>n<\/jats:italic> = 45) and female (<jats:italic>n<\/jats:italic> = 11) patients with HFrEF and healthy\u2010matched male (<jats:italic>n<\/jats:italic> = 24) and female (<jats:italic>n<\/jats:italic> = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with sex\u2010matched controls, complex I mitochondrial oxygen flux was 17% (<jats:italic>P<\/jats:italic> = 0.030) and 29% (<jats:italic>P<\/jats:italic> = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (<jats:italic>r<\/jats:italic> = 0.71; <jats:italic>P<\/jats:italic> &gt; 0.0001). Female HFrEF patients had a 32% (<jats:italic>P<\/jats:italic> = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (<jats:italic>P<\/jats:italic> = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator\u2010activated receptor \u03b3 coactivator\u20101\u03b1, NADH:ubiquinone oxidoreductase core subunit S1\/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data provide novel evidence that HFrEF induces divergent sex\u2010specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial \u2018quantity' in female patients and mitochondrial \u2018quality' in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex\u2010specific mitochondrial abnormalities in skeletal muscle.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12488","type":"journal-article","created":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T22:09:54Z","timestamp":1566338994000},"page":"79-88","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure"],"prefix":"10.1002","volume":"11","author":[{"given":"Jack O.","family":"Garnham","sequence":"first","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee D.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Caspi","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moza M.","family":"Al\u2010Owais","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Bullock","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter P.","family":"Swoboda","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Koshy","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Gierula","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Paton","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Cubbon","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Kearney","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1740-2474","authenticated-orcid":false,"given":"T. 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