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The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism

Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in the endoplasmic reticulum. However, the role of individual arms of the UPR in skeletal...

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Autores principales: Roy, Anirban, Tomaz da Silva, Meiricris, Bhat, Raksha, Bohnert, Kyle R, Iwawaki, Takao, Kumar, Ashok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635982/
https://www.ncbi.nlm.nih.gov/pubmed/34812145
http://dx.doi.org/10.7554/eLife.73215
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author Roy, Anirban
Tomaz da Silva, Meiricris
Bhat, Raksha
Bohnert, Kyle R
Iwawaki, Takao
Kumar, Ashok
author_facet Roy, Anirban
Tomaz da Silva, Meiricris
Bhat, Raksha
Bohnert, Kyle R
Iwawaki, Takao
Kumar, Ashok
author_sort Roy, Anirban
collection PubMed
description Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in the endoplasmic reticulum. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1α or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific ablation of IRE1α dampens Notch signaling and canonical NF-κB pathway in skeletal muscle of adult mice. Finally, targeted ablation of IRE1α also reduces Notch signaling, abundance of satellite cells, and skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our experiments suggest that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.
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spelling pubmed-86359822021-12-03 The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism Roy, Anirban Tomaz da Silva, Meiricris Bhat, Raksha Bohnert, Kyle R Iwawaki, Takao Kumar, Ashok eLife Cell Biology Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in the endoplasmic reticulum. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1α or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific ablation of IRE1α dampens Notch signaling and canonical NF-κB pathway in skeletal muscle of adult mice. Finally, targeted ablation of IRE1α also reduces Notch signaling, abundance of satellite cells, and skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our experiments suggest that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner. eLife Sciences Publications, Ltd 2021-11-23 /pmc/articles/PMC8635982/ /pubmed/34812145 http://dx.doi.org/10.7554/eLife.73215 Text en © 2021, Roy et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Roy, Anirban
Tomaz da Silva, Meiricris
Bhat, Raksha
Bohnert, Kyle R
Iwawaki, Takao
Kumar, Ashok
The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
title The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
title_full The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
title_fullStr The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
title_full_unstemmed The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
title_short The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
title_sort ire1/xbp1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635982/
https://www.ncbi.nlm.nih.gov/pubmed/34812145
http://dx.doi.org/10.7554/eLife.73215
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