CD36 localized on outer mitochondrial membrane represses myogenic differentiation via chronic integrated stress response

The integrated stress response (ISR) plays a vital role in myogenic differentiation of muscle satellite cells. However, the receptor molecule on the outer mitochondrial membrane (OMM) that responds to aging during ISR activation remains unclear. In this study, chronic ISR was induced with impaired myogenic differentiation and cluster of differentiation 36 (CD36) was highly expressed and localized on the OMM in age-related skeletal muscle. Knocking down CD36 expression in differentiated C2C12 myoblasts indicated that Myogenin (MyoG) expression was decreased but Myosin heavy chain 1 (Myh1) expression was increased. Bioinformatics analysis revealed that CD36 is directly related to proteins in the mitochondrial electron transport chain (ETC) subunits and is indirectly associated with proteins involved in the ISR and the mitochondrial unfolded protein response (UPR ^mt ). Following CD36 knockdown, the expression of Succinate dehydrogenase complex flavoprotein subunit a and b (SDHA and SDHB), and ISR related proteins nuclear Activating transcription factor 4 (ATF4) decreased, but UPR ^mt related protein nuclear Activating transcription factor 5 (ATF5) increased. Protein–protein interaction analysis and immunoprecipitation demonstrated that CD36 interacts directly with Mammalian Target of Rapamycin (mTOR). Collectively, age related skeletal muscle was able to induce CD36 localized on the OMM, while CD36/mTOR/ETC-submits was associated with chronic ISR and impaired myogenic differentiation, which could have implications for the development of new strategies to treat sarcopenia.