Swell1 regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism

Ashutosh Kumar, Litao Xie, Chau My Ta, Antentor J. Hinton, Susheel K. Gunasekar, Rachel A. Minerath, Karen Shen, Joshua M. Maurer, Chad E. Grueter, E. Dale Abel, Gretchen Meyer, Rajan Sah

Research output: Contribution to journalArticlepeer-review

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 WT mice. These results reveal that the LRRC8 complex regulates insulin-PI3K-AKT-mTOR signalling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.

Original languageEnglish
Pages (from-to)1-59
Number of pages59
JournaleLife
Volume9
DOIs
StatePublished - Sep 2020

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