Stage-specific effects of Notch activation during skeletal myogenesis

Abstract

Skeletal myogenesis involves sequential activation, proliferation, self-renewal/differentiation and fusion of myogenic stem cells (satellite cells). Notch signaling is known to be essential for the maintenance of satellite cells, but its function in late-stage myogenesis, i.e. post-differentiation myocytes and post-fusion myotubes, is unknown. Using stage-specific Cre alleles, we uncovered distinct roles of Notch1 in mononucleated myocytes and multinucleated myotubes. Specifically, constitutive Notch1 activation dedifferentiates myocytes into Pax7+ quiescent satellite cells, leading to severe defects in muscle growth and regeneration, and postnatal lethality. By contrast, myotube-specific Notch1 activation improves the regeneration and exercise performance of aged and dystrophic muscles. Mechanistically, Notch1 activation in myotubes upregulates the expression of Notch ligands, which modulate Notch signaling in the adjacent satellite cells to enhance their regenerative capacity. These results highlight context-dependent effects of Notch activation during myogenesis, and demonstrate that Notch1 activity improves myotube's function as a stem cell niche.

Data availability

The following previously published data sets were used

Article and author information

Author details

  1. Pengpeng Bi

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Feng Yue

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yusuke Sato

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sara Wirbisky

    School of Health Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Weiyi Liu

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tizhong Shan

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yefei Wen

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2121-7538
  8. Daoguo Zhou

    Department of Biological Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jennifer Freeman

    School of Health Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shihuan Kuang

    Department of Animal Sciences, Purdue University, West Lafayette, United States
    For correspondence
    skuang@purdue.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9180-3180

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR060652)

  • Shihuan Kuang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures involving mice were approved by Purdue University's Animal Care and Use Committee under protocol # 1112000440.

Reviewing Editor

  1. Anne C Ferguson-Smith, University of Cambridge, United Kingdom

Publication history

  1. Received: May 2, 2016
  2. Accepted: September 17, 2016
  3. Accepted Manuscript published: September 19, 2016 (version 1)
  4. Version of Record published: October 19, 2016 (version 2)
  5. Version of Record updated: August 8, 2017 (version 3)

Copyright

© 2016, Bi 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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  1. Pengpeng Bi
  2. Feng Yue
  3. Yusuke Sato
  4. Sara Wirbisky
  5. Weiyi Liu
  6. Tizhong Shan
  7. Yefei Wen
  8. Daoguo Zhou
  9. Jennifer Freeman
  10. Shihuan Kuang
(2016)
Stage-specific effects of Notch activation during skeletal myogenesis
eLife 5:e17355.
https://doi.org/10.7554/eLife.17355

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