1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism

  1. Anirban Roy
  2. Meiricris Tomaz da Silva
  3. Raksha Bhat
  4. Kyle R Bohnert
  5. Takao Iwawaki
  6. Ashok Kumar  Is a corresponding author
  1. University of Houston, United States
  2. St Ambrose University, United States
  3. Kanazawa Medical University, Japan
Research Article
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Cite this article as: eLife 2021;10:e73215 doi: 10.7554/eLife.73215

Abstract

Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways activated in both injured myofibers and satellite cells. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1 or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific deletion of IRE1α dampens Notch signaling and canonical NF-kB pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1α reduces skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Anirban Roy

    Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Meiricris Tomaz da Silva

    Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Raksha Bhat

    Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kyle R Bohnert

    Kinesiology Department, St Ambrose University, Davenport, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Takao Iwawaki

    Division of Cell Medicine, Department of Life Science, Kanazawa Medical University, Uchinada, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Ashok Kumar

    Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, United States
    For correspondence
    akumar43@central.uh.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8571-2848

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059810)

  • Ashok Kumar

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR068313)

  • Ashok Kumar

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 strict 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 approved institutional animal care and use committee (IACUC) protocol (PROT20190043) of the University of Houston. All surgery was performed under Isoflurane, and every effort was made to minimize suffering.

Reviewing Editor

  1. Christopher Cardozo

Publication history

  1. Received: August 20, 2021
  2. Accepted: November 22, 2021
  3. Accepted Manuscript published: November 23, 2021 (version 1)

Copyright

© 2021, Roy 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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