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Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1\u03b1 levels in muscle and the potential mechanisms involved.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Palmitate- or tunicamycin-induced ER stress resulted in PGC-1\u03b1 downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1\u03b1 expression, whereas ATF4 knockdown abrogated the reduction of PCG-1\u03b1 caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1\u03b1 transcription. The mTOR inhibitor torin 1 restored PCG-1\u03b1 and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1\u03b1 caused by the ER stressor tunicamycin.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1\u03b1 transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states.<\/jats:p>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12964-022-00865-9","type":"journal-article","created":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T11:02:53Z","timestamp":1650020573000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Endoplasmic reticulum stress downregulates PGC-1\u03b1 in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2"],"prefix":"10.1186","volume":"20","author":[{"given":"Marta","family":"Montori-Grau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Aguilar-Recarte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Zarei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Pizarro-Delgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Palomer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"V\u00e1zquez-Carrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,15]]},"reference":[{"key":"865_CR1","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.tem.2015.05.007","volume":"26","author":"L Salvad\u00f3","year":"2015","unstructured":"Salvad\u00f3 L, Palomer X, Barroso E, V\u00e1zquez-Carrera M. 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