SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism

Author:

Kumar Ashutosh1,Xie Litao1,Ta Chau My1,Hinton Antentor O23,Gunasekar Susheel K1,Minerath Rachel A24,Shen Karen5,Maurer Joshua M1,Grueter Chad E24,Abel E Dale23ORCID,Meyer Gretchen5,Sah Rajan1ORCID

Affiliation:

1. Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States

2. Fraternal Order of Eagles Diabetes Research Center, Iowa City, United States

3. Division of Endocrinology and Metabolism, Iowa City, United States

4. Division of Cardiology, University of Iowa, Iowa City, United States

5. Program in Physical Therapy and Departments of Neurology, Biomedical Engineering and Orthopedic Surgery, Washington University in St. Louis, St. Louis, United States

Abstract

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 (Lrrc8a) 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 Lrrc8a KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle-targeted Lrrc8a 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.

Funder

National Institutes of Health

Roy J. Carver Charitable Trust

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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