AMPK mediates early activation of the unfolded protein response through a positive feedback loop in palmitate-treated muscle cells

Abstract

AbstractActivation of the unfolded protein response (UPR) is closely associated with the pathogenesis of many metabolic diseases including obesity and type 2 diabetes. There is increasing evidence for the interdependence of the UPR and metabolic signaling pathways. The AMP-activated protein kinase (AMPK) signaling pathway controls energy balance in eukaryotes. The aim of this study was to investigate the possible interaction between AMPK signaling and the UPR in muscle cells exposed to a saturated fatty acid, as well as the underlying mechanism. The UPR was induced in C2C12 myotubes by treatment with palmitate along with activation of AMPK signaling. Inhibiting the AMPK pathway with compound C attenuated palmitate-induced UPR activation, while inhibiting the UPR with taurourdodeoxycholic acid alleviated palmitate-induced AMPK activation, suggesting a positive feedback loop between the UPR and AMPK. Additionally, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide, an AMPK agonist, caused a dose- and time-dependent upregulation of genes related to the UPR, including activating transcription factor (ATF)4, binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible protein (GADD)34. These results provide the first evidence for the involvement of AMPK signaling in the early activation of the UPR induced by saturated fatty acid in skeletal muscle, and suggest that physiologic or pharmacologic activation of the AMPK pathway (ie, by exercise or metformin, respectively) can promote skeletal muscle health and function and thus improve quality of life for individuals with metabolic disorder due to a high-fat diet or obesity.