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http://purl.uniprot.org/citations/35428325http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35428325http://www.w3.org/2000/01/rdf-schema#comment"

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. Video Abstract."xsd:string
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http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/author"Montori-Grau M."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/author"Zarei M."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/author"Palomer X."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/author"Vazquez-Carrera M."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/author"Pizarro-Delgado J."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/author"Aguilar-Recarte D."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/date"2022"xsd:gYear
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/name"Cell Commun Signal"xsd:string
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http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/title"Endoplasmic reticulum stress downregulates PGC-1alpha in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2."xsd:string
http://purl.uniprot.org/citations/35428325http://purl.uniprot.org/core/volume"20"xsd:string
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