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Endoplasmic reticulum stress downregulates PGC-1α in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2 Montori Grau, Marta Aguilar, David Zarei, Mohammad Pizarro Delgado, Javier Palomer Tarridas, Francesc Xavier Vázquez Carrera, Manuel Reticle endoplasmàtic Diabetis Resistència a la insulina Endoplasmic reticulum Diabetes Insulin resistance Background Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. Methods The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. Results Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α 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-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. Conclusions Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. 2022-04-28T12:28:35Z 2022-04-28T12:28:35Z 2022-04-15 2022-04-28T12:28:36Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1186/s12964-022-00865-9 Cell Communication and Signaling, 2022, vol. 20, p. 53 https://doi.org/10.1186/s12964-022-00865-9 cc-by (c) Montori Grau, Marta et al., 2022 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess BioMed Central Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)