Irisin counteracts high glucose and fatty acid induced cytotoxicity by preserving AMPK-insulin receptor signaling axis in C2C12 myoblast.

Irisin, a newly identified myokine, is critical to modulating metabolism and biological homeostasis. However, whether irisin protects the skeletal muscles against the metabolic stresses remains unknown. In this study, we determine the effect of irisin on high glucose and fatty acid induced damages using irisin overexpressed mouse C2C12 myoblast (Irisin-C2C12) and skeletal muscle from irisin-injected mice. As compared to empty vector transfected control, irisin overexpression resulted in a marked increase of cell viability and decrease of apoptosis under high glucose stress. Progression of cell cycle into G2/M phase under proliferative condition was observed by irisin overexpression. Furthermore, glucose uptake, glycogen accumulation and phosphorylation of AMPKalpha / insulin receptor beta subunit (IRbeta) / Erk1/2 in response to insulin stimulation were enhanced by irisin overexpression. In irisin-C2C12 myoblasts, these responses of phosphorylation were preserved under palmitate (PA) treatment which induced insulin resistance. These effects of irisin were reversed by inhibiting AMPK with compound C. Additionally, high glucose-induced suppression of mitochondrial membrane potential was also prevented by irisin. Moreover, suppression of IR in Irisin-C2C12 myoblasts by co-transfection of shRNA against IR also mitigated the effects of irisin while not affecting the AMPKalpha phosphorylation. Furthermore, soleus muscles from irisin injected mice showed elevated phosphorylation of AMPKalpha and Erk1/2 and glycogen contents. Our results indicate that irisin counteracts to the stresses generated by high glucose and fatty acid and serves as a novel approach to eliciting cellular protection. Furthermore, AMPK activation is a crucial factor which regulates insulin action as a downstream target.