Endoplasmic reticulum stress downregulates PGC-1a in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2
Background: Peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha) 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-1 alpha levels in mu...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Fundació Sant Joan de Déu |
| Repositorio: | r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu |
| OAI Identifier: | oai:fsjd.fundanetsuite.com:p21391 |
| Acceso en línea: | https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=21391 |
| Access Level: | acceso abierto |
| Palabra clave: | ER stress PGC-1 alpha mTOR CRTC2 IRS1 Skeletal muscle |
| Sumario: | Background: Peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha) 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-1 alpha 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-1 alpha downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1 alpha expression, whereas ATF4 knockdown abrogated the reduction of PCG-1 alpha 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 alpha transcription. The mTOR inhibitor torin 1 restored PCG-1 alpha and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1 alpha caused by the ER stressor tunicamycin. Conclusions: Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1 alpha transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. |
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