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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 IRE1\u03b1 (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1\u03b1 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 IRE1\u03b1 reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific ablation of IRE1\u03b1 dampens Notch signaling and canonical NF-\u03baB pathway in skeletal muscle of adult mice. Finally, targeted ablation of IRE1\u03b1 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 IRE1\u03b1-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.<\/jats:p>","DOI":"10.7554\/elife.73215","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T07:15:12Z","timestamp":1637651712000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.73215","source":"Crossref","is-referenced-by-count":27,"title":["The IRE1\/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5625-5403","authenticated-orcid":true,"given":"Anirban","family":"Roy","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7479-2595","authenticated-orcid":true,"given":"Meiricris","family":"Tomaz da Silva","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raksha","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle R","family":"Bohnert","sequence":"additional","affiliation":[{"name":"Kinesiology Department, St Ambrose University","place":["Davenport, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Iwawaki","sequence":"additional","affiliation":[{"name":"Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University","place":["Uchinada, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-2848","authenticated-orcid":true,"given":"Ashok","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.ejcb.2018.05.002","article-title":"The unknown face of IRE1\u03b1 - 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