1. Cell Biology
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SWELL1 regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism

  1. Ashutosh Kumar
  2. Litao Xie
  3. Chau My Ta
  4. Antentor J Hinton
  5. Susheel K Gunasekar
  6. Rachel A Minerath
  7. Karen Shen
  8. Joshua M Maurer
  9. Chad E Grueter
  10. E Dale Abel
  11. Gretchen Meyer
  12. Rajan Sah  Is a corresponding author
  1. Washington University, United States
  2. Washington University School of Medicine, United States
  3. University of Iowa, United States
Research Article
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Cite this article as: eLife 2020;9:e58941 doi: 10.7554/eLife.58941

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.

Article and author information

Author details

  1. Ashutosh Kumar

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Litao Xie

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chau My Ta

    Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Antentor J Hinton

    Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa city, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Susheel K Gunasekar

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Rachel A Minerath

    Fraternal Order of Eagles Diabetes Research Center, Division of Cardiology, University of Iowa, Iowa city, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Karen Shen

    Program in Physical Therapy and Departments of Neurology, Biomedical Engineering and Orthopedic Surgery, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joshua M Maurer

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Chad E Grueter

    Fraternal Order of Eagles Diabetes Research Center,Division of Cardiology, University of Iowa, Iowa city, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. E Dale Abel

    Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5290-0738
  11. Gretchen Meyer

    Program in Physical Therapy and Departments of Neurology, Biomedical Engineering and Orthopedic Surgery, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Rajan Sah

    Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States
    For correspondence
    rajan.sah@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1092-1244

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.

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).

Reviewing Editor

  1. Muthu Periasamy

Publication history

  1. Received: May 14, 2020
  2. Accepted: September 7, 2020
  3. Accepted Manuscript published: September 15, 2020 (version 1)

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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