The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration
- University of Louisville School of Medicine, United States
- duPont Manual High School, United States
- Pennsylvania State University, United States
- University of Louisville School of Medicine,, United States
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.
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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
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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The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration
eLife 6:e22871.
https://doi.org/10.7554/eLife.22871
