Chiglitazar prevents diabetes-induced skeletal muscle loss by enhancing myogenic differentiation through the MEK/ERK pathway

Long term diabetes significantly deteriorates skeletal muscle mass and function, leading to adverse outcomes. Chiglitazar (CHI), a pan-PPAR agonist, effectively lowers blood glucose levels and inhibits lipid synthesis. This study investigated CHI's protective effects against muscle loss in type 2 diabetes (T2D) using clinical data and an in vitro model with C2C12 myoblasts exposed to high glucose (HG) conditions. In vivo efficacy was assessed in the db/db mouse model. Clinical studies showed CHI enhances muscle quality and strength. In vitro, HG suppressed myotube fusion, while CHI reversed this effect by upregulating myogenic differentiation molecules. RNA sequencing indicated that CHI's protective effects are mediated by the phosphorylation of the MEK/ERK signaling pathway, which was further confirmed by Western blot analysis. Additionally, the use of U0126, a specific MEK/ERK inhibitor, demonstrated that inhibiting this pathway significantly diminished the protective effects of CHI on myoblast differentiation, providing further evidence of the critical role of the MEK/ERK pathway in mediating CHI's beneficial effects. In db/db mice, CHI reduced diabetes-associated muscle loss and improved grip strength. These findings suggest CHI mitigates diabetes-induced muscle loss by enhancing myogenic differentiation via the MEK/ERK pathway, highlighting its potential as a therapeutic agent.