{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:03:24Z","timestamp":1790129004248,"version":"4.0.1"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,3,19]],"date-time":"2022-03-19T00:00:00Z","timestamp":1647648000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["U54GM104940"],"award-info":[{"award-number":["U54GM104940"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011073","name":"Nutrition Obesity Research Center, University of North Carolina","doi-asserted-by":"publisher","award":["P30DK072476"],"award-info":[{"award-number":["P30DK072476"]}],"id":[{"id":"10.13039\/100011073","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial\u2010targeted furazano[3,4\u2010b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet\u2010induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eighty\u2010week\u2010old male C57BL\/6J mice with obesity were randomized to 10\u00a0weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w\/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>BAM15 decreased body weight (54.0\u00a0\u00b1\u00a02.0 vs. 42.3\u00a0\u00b1\u00a01.3\u00a0g, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) which was attributable to increased energy expenditure (10.1\u00a0\u00b1\u00a00.1 vs. 11.3\u00a0\u00b1\u00a00.4\u00a0kcal\/day, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). BAM15 increased muscle mass (52.7\u00a0\u00b1\u00a00.4 vs. 59.4\u00a0\u00b1\u00a01.0%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), strength (91.1\u00a0\u00b1\u00a01.3 vs. 124.9\u00a0\u00b1\u00a01.2\u00a0g, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), and locomotor activity (347.0\u00a0\u00b1\u00a014.4 vs. 432.7\u00a0\u00b1\u00a032.0\u00a0m, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1\u2010ubiquitin binding and LC3II, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), increased mitochondrial activity (citrate synthase and complex II activity, all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble\/soluble ratio, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) while limiting ER stress (decreased PERK signalling, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), apoptotic signalling (decreased cytochrome C release and Caspase\u20103\/9 activation, all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), and muscle protein degradation (decreased 14\u2010kDa actin fragment insoluble\/soluble ratio, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Mitochondrial uncoupling by agents such as BAM15 may mitigate age\u2010related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12982","type":"journal-article","created":{"date-parts":[[2022,3,19]],"date-time":"2022-03-19T10:45:11Z","timestamp":1647686711000},"page":"1821-1836","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control"],"prefix":"10.1002","volume":"13","author":[{"given":"Wagner S.","family":"Dantas","sequence":"first","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth R.M.","family":"Zunica","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Heintz","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolormaa","family":"Vandanmagsar","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. Elizabeth","family":"Floyd","sequence":"additional","affiliation":[{"name":"Ubiquitin Biology Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongmei","family":"Yu","sequence":"additional","affiliation":[{"name":"Ubiquitin Biology Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Cryo\u2010Electron Microscopy Core Case Western Reserve University  Cleveland OH USA"},{"name":"Center for Mitochondrial Diseases Case Western Reserve University of School of Medicine  Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Hoppel","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"},{"name":"Center for Mitochondrial Diseases Case Western Reserve University of School of Medicine  Cleveland OH USA"},{"name":"Department of Pharmacology Case Western Reserve University  Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn P.","family":"Belmont","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Axelrod","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center  Baton Rouge LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7321-9917","authenticated-orcid":false,"given":"John P.","family":"Kirwan","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine 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