Dichloroacetate, a pyruvate dehydrogenase activator, alleviates high‐fat‐induced impairment of myogenic differentiation in skeletal muscles

Abstract Obesity‐induced impairment of myogenic differentiation leads to muscle loss and sarcopenia. Pyruvate dehydrogenase (PDH) plays a crucial role in glucose metabolism and is associated with muscle differentiation. However, the effect of dichloroacetate (DCA), a PDH activator, on obesity‐induced impairment of myogenic differentiation remains unknown. Here, we evaluated the effects of DCA treatment on high‐fat intake‐induced impairment of myogenic differentiation in C2C12 cells and C57BL/6 mice. In C2C12 cells, DCA treatment improved PDH activity that was reduced by palmitate (PAL) and decreased the lactate concentrations in the media. Additionally, DCA reversed PAL‐ and high‐fat diet (HFD)‐induced decrease in the expression of myoblast determination protein 1 (MyoD), myogenin (MyoG) and myosin heavy chain (MyHC) in C2C12 cells and C57BL/6 mice. To explore the possible mechanism, DCA treatment restored the levels of p‐Akt, p‐FoxO1, p‐FoxO3a and p‐p38 MAPK levels in PAL‐treated C2C12 cells. Moreover, the protective effects of DCA were reversed by treatment with the Akt inhibitor MK2206 in C2C12 cells. In summary, DCA treatment alleviated high‐fat intake‐induced impairment of myogenic differentiation via Akt signalling, suggesting its potential in treating obesity‐associated muscle loss and sarcopenia.