<p>The integrated stress response (ISR) and mitochondrial unfolded protein response (UPR^mt) plays a vital role in myogenic differentiation of muscle satellite cells. In this study, chronic ISR and UPR^mt was induced with impaired myogenic differentiation and cluster of differentiation 36 (CD36) was highly expressed and localized on the mitochondria in aging muscle. Little is known about the interplay of CD36 and ISR during differentiation. Knocking down CD36 expression at day 3 in differentiated C2C12 myoblasts indicated that the expression levels of Activating transcription factor 4 (ATF4), and other ISR - related proteins decreased, but the expression levels of UPR^mt - related proteins Activating transcription factor 5 (ATF5), Heat Shock Protein 60(HSP60) and Heat Shock Protein 10(HSP10) increased with mRNA level of HSP60 increased. Meanwhile Myogenin (MyoG) expression level was increased but Myosin heavy chain 1 (Myh1) expression level was decreased. Following CD36 knockdown, mito-nuclear protein imbalance and mitochondrial dysfunction occurred. Interaction between CD36 and Mammalian Target of Rapamycin (mTOR) was observed in aging muscle. Collectively, CD36 was localized on the mitochondria in aging muscle, while CD36 was associated with ISR and UPR^mt early during myogenic differentiation in C2C12 myoblasts, which could have implications for the development of new strategies to treat sarcopenia.</p>