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

Long-term diabetes markedly impairs skeletal muscle mass and function, contributing to adverse clinical outcomes. Chiglitazar (CHI), a pan-PPAR agonist, effectively reduces blood glucose levels and suppresses lipid synthesis. This study examined the protective effects of CHI against muscle loss in type 2 diabetes (T2D) using clinical data and an in vitro model involving C2C12 myoblasts cultured under high-glucose (HG) conditions. In vivo efficacy was evaluated in db/db mice. Clinical analyses revealed that CHI improves muscle quality and strength. In vitro, HG conditions inhibited myotube fusion, whereas CHI counteracted this suppression by upregulating key molecules involved in myogenic differentiation. RNA sequencing suggested that CHI exerts its protective influence through phosphorylation of the MEK/ERK signaling pathway-a finding corroborated by Western blot. Moreover, treatment with U0126, a selective MEK/ERK inhibitor, substantially attenuated the protective effects of CHI on myoblast differentiation, underscoring the essential role of this pathway. In db/db mice, CHI alleviated diabetes-related muscle loss and enhanced grip strength. These results indicate that CHI protects against diabetes-induced muscle loss by promoting myogenic differentiation via the MEK/ERK pathway, supporting its potential as a therapeutic intervention.