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Carver Charitable Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (\n                    <jats:italic>Lrrc8a<\/jats:italic>\n                    ) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1\/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. LRRC8A over-expression in\n                    <jats:italic>Lrrc8a<\/jats:italic>\n                    KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle-targeted\n                    <jats:italic>Lrrc8a<\/jats:italic>\n                    KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to wild-type (WT) mice. These results reveal that the LRRC8 complex regulates insulin-PI3K-AKT-mTOR signaling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.\n                  <\/jats:p>","DOI":"10.7554\/elife.58941","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T06:00:28Z","timestamp":1600149628000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.58941","source":"Crossref","is-referenced-by-count":69,"title":["SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism"],"prefix":"10.7554","volume":"9","author":[{"given":"Ashutosh","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United 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Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A","family":"Minerath","sequence":"additional","affiliation":[{"name":"Fraternal Order of Eagles Diabetes Research Center, Iowa City, United States"},{"name":"Division of Cardiology, University of Iowa, Iowa City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Shen","sequence":"additional","affiliation":[{"name":"Program in Physical Therapy and Departments of Neurology, Biomedical Engineering and Orthopedic Surgery, Washington University in St. Louis, St. Louis, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M","family":"Maurer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad E","family":"Grueter","sequence":"additional","affiliation":[{"name":"Fraternal Order of Eagles Diabetes Research Center, Iowa City, United States"},{"name":"Division of Cardiology, University of Iowa, Iowa City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5290-0738","authenticated-orcid":true,"given":"E Dale","family":"Abel","sequence":"additional","affiliation":[{"name":"Fraternal Order of Eagles Diabetes Research Center, Iowa City, United States"},{"name":"Division of Endocrinology and Metabolism, Iowa City, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Meyer","sequence":"additional","affiliation":[{"name":"Program in Physical Therapy and Departments of Neurology, Biomedical Engineering and Orthopedic Surgery, Washington University in St. Louis, St. Louis, United 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