Endoplasmic reticulum stress downregulates PGC-1α 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 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.

Automated summary

This study found that endoplasmic reticulum (ER) stress downregulates the expression of PGC-1 alpha in skeletal muscle through the activation of ATF4 and the mTOR-CRTC2 pathway. These findings suggest that inhibition of ATF4 and the mTOR-CRTC2 axis could be a therapeutic target for insulin resistant states.