Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration
- University of Rochester Medical Center, United States
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.
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Author details
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).
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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Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration
eLife 5:e19484.
https://doi.org/10.7554/eLife.19484
