1. Stem Cells and Regenerative Medicine
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Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration

  1. Nicole D Paris
  2. Andrew Soroka
  3. Alanna Klose
  4. Wenxuan Liu
  5. Joe V Chakkalakal  Is a corresponding author
  1. University of Rochester Medical Center, United States
Research Article
  • Cited 17
  • Views 1,810
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Cite this article as: eLife 2016;5:e19484 doi: 10.7554/eLife.19484

Abstract

Skeletal muscle regenerative potential declines with age, in part due to deficiencies in resident stem cells (satellite cells, SCs) and derived myogenic progenitors (MPs); however, the factors responsible for this decline remain obscure. TGFβ superfamily signaling is an inhibitor of myogenic differentiation, with elevated activity in aged skeletal muscle. Surprisingly, we find reduced expression of Smad4, the downstream cofactor for canonical TGFβ superfamily signaling, and the target Id1 in aged SCs and MPs during regeneration. Specific deletion of Smad4 in adult mouse SCs led to increased propensity for terminal myogenic commitment connected to impaired proliferative potential. Furthermore, SC-specific Smad4 disruption compromised adult skeletal muscle regeneration. Finally, loss of Smad4 in aged SCs did not promote aged skeletal muscle regeneration. Therefore, SC-specific reduction of Smad4 is a feature of aged regenerating skeletal muscle and Smad4 is a critical regulator of SC and MP amplification during skeletal muscle regeneration.

Article and author information

Author details

  1. Nicole D Paris

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0654-0983
  2. Andrew Soroka

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alanna Klose

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Wenxuan Liu

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joe V Chakkalakal

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    For correspondence
    joe_chakkalakal@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8440-7312

Funding

University of Rochester Medical Center (Start-up Funds)

  • Joe V Chakkalakal

National Institutes of Health (R01AG051456)

  • Joe V Chakkalakal

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. Work with mice was conducted in accordance with protocols approved by the University Committee on Animal Resources, University of Rochester Medical Center (Protocol #101565/2013-002).

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: July 11, 2016
  2. Accepted: November 16, 2016
  3. Accepted Manuscript published: November 18, 2016 (version 1)
  4. Version of Record published: December 5, 2016 (version 2)

Copyright

© 2016, Paris 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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