SWELL1 regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism
- Washington University, United States
- Washington University School of Medicine, United States
- University of Iowa, 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 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.
Data availability
We have uploaded the RNA sequencing data file in GEO (accession code: Series GSE156667 )
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Effect of SWELL1 (LRRC8a) gene deletion on gene expression in differentiated myotubesNCBI Gene Expression Omnibus, GSE156667.
Article and author information
Author details
Funding
National Institutes of Health (1R01DK106009)
- Rajan Sah
National Institutes of Health (R01HL125436)
- Chad E Grueter
National Institutes of Health (RO1HL127764)
- E Dale Abel
National Institutes of Health (RO1HL112413)
- E Dale Abel
National Institutes of Health (1P30AR074992-01)
- Rajan Sah
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Muthu Periasamy
Ethics
Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the approved institutional animal care and use committee (IACUC) protocols of Washington University in St. Louis (20180217) and the University of Iowa (1308148).
Version history
- Received: May 14, 2020
- Accepted: September 7, 2020
- Accepted Manuscript published: September 15, 2020 (version 1)
- Accepted Manuscript updated: September 28, 2020 (version 2)
- Version of Record published: October 7, 2020 (version 3)
Copyright
© 2020, Kumar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SWELL1 regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism
eLife 9:e58941.
https://doi.org/10.7554/eLife.58941
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