1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration

  1. Guangyan Xiong
  2. Sajedah M Hindi
  3. Aman K Mann
  4. Yann Simon Gallot
  5. Kyle R Bohnert
  6. Douglas R Cavener
  7. Scott R Whittemore
  8. Ashok Kumar  Is a corresponding author
  1. University of Louisville School of Medicine, United States
  2. duPont Manual High School, United States
  3. Pennsylvania State University, United States
  4. University of Louisville School of Medicine,, United States
Research Article
  • Cited 23
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Cite this article as: eLife 2017;6:e22871 doi: 10.7554/eLife.22871

Abstract

Regeneration of skeletal muscle in adults is mediated by satellite stem cells. Accumulation of misfolded proteins triggers endoplasmic reticulum stress that leads to unfolded protein response (UPR). The UPR is relayed to the cell through the activation of PERK, IRE1/XBP1, and ATF6. Here, we demonstrate that levels of PERK and IRE1 are increased in satellite cells upon muscle injury. Inhibition of PERK, but not the IRE1 arm of the UPR in satellite cells inhibits myofiber regeneration in adult mice. PERK is essential for the survival and differentiation of activated satellite cells into the myogenic lineage. Deletion of PERK causes hyper-activation of p38 MAPK during myogenesis. Blocking p38 MAPK activity improves the survival and differentiation of PERK-deficient satellite cells in vitro and muscle formation in vivo. Collectively, our results suggest that the PERK arm of the UPR plays a pivotal role in the regulation of satellite cell homeostasis during regenerative myogenesis.

Article and author information

Author details

  1. Guangyan Xiong

    Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sajedah M Hindi

    Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aman K Mann

    duPont Manual High School, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yann Simon Gallot

    Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4447-1448
  5. Kyle R Bohnert

    Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Douglas R Cavener

    Eberly College of Science, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Scott R Whittemore

    Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine,, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ashok Kumar

    Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine,, Louisville, United States
    For correspondence
    ashok.kumar@louisville.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,AR068313)

  • Ashok Kumar

National Institute on Aging (AG029623)

  • 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) protocols (#13097) of the University of Louisville. All surgery was performed under anesthesia, and every effort was made to minimize suffering

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: November 1, 2016
  2. Accepted: March 21, 2017
  3. Accepted Manuscript published: March 23, 2017 (version 1)
  4. Version of Record published: April 13, 2017 (version 2)

Copyright

© 2017, Xiong 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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