Endoplasmic reticulum stress downregulates PGC-1a in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2
Por:
Montori M, Aguilar-Recarte D, Zarei M, Pizarro J, Palomer FX and Vazquez M
Publicada:
15 abr 2022
Ahead of Print:
15 abr 2022
Resumen:
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.
Filiaciones:
Montori M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
Aguilar-Recarte D:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Zarei M:
John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, USA
Pizarro J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Palomer FX:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
Unitat de Farmacologia, Facultat de Farmàcia i Ciències de l'Alimentació, Av. Joan XXIII 27-31, 08028, Barcelona, Spain.
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