The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration.
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.
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.
Guangyan
G
Xiong
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.
Sajedah M
SM
Hindi
duPont Manual High School, Louisville, United States.
Aman K
AK
Mann
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.
Yann S
http://orcid.org/0000-0003-4447-1448
YS
Gallot
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.
Kyle R
KR
Bohnert
Eberly College of Science, Pennsylvania State University, University Park, United States.
Douglas R
DR
Cavener
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.|Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, United States.
Scott R
SR
Whittemore
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.
Ashok
http://orcid.org/0000-0001-8571-2848
A
Kumar
D000818:Animals; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000293:injuries / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism*
D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C486556:Ern2 protein, mouse
ER Stress; IRE1/XBP1; PERK; cell biology; developmental biology; mouse; satellite cells; skeletal muscle regeneration; stem cells; survival