{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T14:17:55Z","timestamp":1788617875807,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2018,8,28]],"date-time":"2018-08-28T00:00:00Z","timestamp":1535414400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH R35 HL135736"],"award-info":[{"award-number":["NIH R35 HL135736"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["1I01BX002567\u201001"],"award-info":[{"award-number":["1I01BX002567\u201001"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Hepatic mitochondrial adaptations to physical activity may be regulated by mitochondrial biogenesis (PGC1\u03b1) and mitophagy (BNIP3). Additionally, these adaptations may be sex\u2010dependent.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Chronic increase in physical activity lowers basal mitochondrial respiratory capacity in mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Female mice have higher hepatic electron transport system protein content, elevated respiratory capacity, lowered mitophagic flux, and emit less mitochondrial H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> independent of physical activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Males require chronic daily physical activity to attain a similar mitochondrial phenotype compared to females. In contrast, females have limited hepatic adaptations to chronic physical activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Livers deficient in PGC1\u03b1 and BNIP3 display similar mitochondrial adaptations to physical activity to those found in wild\u2010type mice.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Hepatic mitochondrial adaptations to physical activity may be regulated by biogenesis\u2010 and mitophagy\u2010associated pathways in a sex\u2010dependent manner. Here, we tested if mice with targeted deficiencies in liver\u2010specific peroxisome proliferator\u2010activated receptor \u03b3 coactivator 1\u03b1 (PGC1\u03b1; LPGC1\u03b1<jats:sup>+\/\u2212<\/jats:sup>) and BCL2\/adenovirus E1B 19 kDa protein\u2010interacting protein 3 (BNIP3)\u2010mediated mitophagy (BNIP3<jats:sup>\u2212\/\u2212<\/jats:sup>) would have reduced physical activity\u2010induced adaptations in respiratory capacity, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> emission and mitophagy compared to wild\u2010type (WT) controls and if these effects were impacted by sex. Male and female WT, LPGC1\u03b1<jats:sup>+\/\u2212<\/jats:sup> and BNIP3<jats:sup>\u2212\/\u2212<\/jats:sup> C57BL6\/J mice were divided into groups that remained sedentary or had access to daily physical activity via voluntary wheel running (VWR) (<jats:italic>n<\/jats:italic>\u00a0= 6\u201310\/group) for 4\u00a0weeks. Mice had <jats:italic>ad libitum<\/jats:italic> access to low\u2010fat diet and water. VWR reduced basal mitochondrial respiration, increased mitochondrial coupling and altered ubiquitin\u2010mediated mitophagy in a sex\u2010specific manner in WT mice. Female mice of all genotypes displayed higher electron transport system content, displayed increased ADP\u2010stimulated respiration, produced less mitochondrially derived reactive oxygen species, exhibited reduced mitophagic flux, and were less responsive to VWR compared to males. Males responded more robustly to VWR\u2010induced changes in hepatic mitochondrial function resulting in a match to adaptations found in females. Deficiencies in PGC1\u03b1 and BNIP3 alone did not largely alter mitochondrial adaptations to VWR. However, VWR restored sex\u2010dependent abnormalities in mitophagic flux in LPGC1\u03b1<jats:sup>+\/\u2212<\/jats:sup>. Finally, BNIP3<jats:sup>\u2212\/\u2212<\/jats:sup> mice had elevated mitochondrial content and increased mitochondrial respiration putatively through repressed mitophagic flux. In conclusion, hepatic mitochondrial adaptations to physical activity are more dependent on sex than PGC1\u03b1 and BNIP3.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276539","type":"journal-article","created":{"date-parts":[[2018,7,31]],"date-time":"2018-07-31T08:30:28Z","timestamp":1533025828000},"page":"6157-6171","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Hepatic mitochondrial adaptations to physical activity: impact of sexual dimorphism, PGC1\u03b1 and BNIP3\u2010mediated mitophagy"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5688-590X","authenticated-orcid":false,"given":"Alex","family":"Von Schulze","sequence":"first","affiliation":[{"name":"Molecular and Integrative Physiology University of Kansas Medical Center  Kansas City KS 66160 USA"},{"name":"Kansas City VA Medical Center  Kansas City MO 64128 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8557-6441","authenticated-orcid":false,"given":"Colin S.","family":"McCoin","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology University of Kansas Medical Center  Kansas City KS 66160 USA"},{"name":"Kansas City VA Medical Center  Kansas City MO 64128 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiemela","family":"Onyekere","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology University of Kansas Medical Center  Kansas City KS 66160 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Allen","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology University of Kansas Medical Center  Kansas City KS 66160 USA"},{"name":"Kansas City VA Medical Center  Kansas City MO 64128 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-7246","authenticated-orcid":false,"given":"Paige","family":"Geiger","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology University of Kansas Medical Center  Kansas City KS 66160 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Gerald W.","family":"Dorn","sequence":"additional","affiliation":[{"name":"Center for Pharmacogenomics Department of Internal Medicine Washington University School of Medicine  St Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7046-3623","authenticated-orcid":false,"given":"E. 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