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未折叠蛋白反应的PERK分支调节卫星细胞介导的骨骼肌再生。

The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration.

作者信息

Xiong Guangyan, Hindi Sajedah M, Mann Aman K, Gallot Yann S, Bohnert Kyle R, Cavener Douglas R, Whittemore Scott R, Kumar Ashok

机构信息

Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, United States.

duPont Manual High School, Louisville, United States.

出版信息

Elife. 2017 Mar 23;6:e22871. doi: 10.7554/eLife.22871.

DOI:10.7554/eLife.22871
PMID:28332979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5391206/
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.

摘要

成体骨骼肌的再生由卫星干细胞介导。错误折叠蛋白的积累引发内质网应激，进而导致未折叠蛋白反应（UPR）。UPR通过PERK、IRE1/XBP1和ATF6的激活传递至细胞。在此，我们证明肌肉损伤后卫星细胞中PERK和IRE1的水平升高。抑制卫星细胞中的PERK而非UPR的IRE1分支会抑制成年小鼠的肌纤维再生。PERK对于激活的卫星细胞存活并分化为肌源性谱系至关重要。PERK的缺失会导致成肌过程中p38 MAPK的过度激活。阻断p38 MAPK活性可改善PERK缺陷型卫星细胞在体外的存活和分化以及体内的肌肉形成。总体而言，我们的结果表明UPR的PERK分支在再生性成肌过程中卫星细胞内稳态的调节中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/0e2da4ca2977/elife-22871-fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/53c3c9fa033f/elife-22871-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/1a12bc4ebdde/elife-22871-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/60f571552fcf/elife-22871-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/913d816f2c48/elife-22871-fig4-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/4cdc0835d567/elife-22871-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/bc9fe1885d75/elife-22871-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/18a76aefec6c/elife-22871-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/529d45b063af/elife-22871-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/0e2da4ca2977/elife-22871-fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/53c3c9fa033f/elife-22871-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/12b93b8f663d/elife-22871-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/dafef3ed5958/elife-22871-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/3db3e0481a64/elife-22871-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/1a12bc4ebdde/elife-22871-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/60f571552fcf/elife-22871-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/913d816f2c48/elife-22871-fig4-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/4cdc0835d567/elife-22871-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/bc9fe1885d75/elife-22871-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/18a76aefec6c/elife-22871-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/529d45b063af/elife-22871-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d986/5391206/0e2da4ca2977/elife-22871-fig9.jpg

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