C2C12: A Cell Model for Studying the Influence of Mitochondria-Induced Integrated Stress Response on Postnatal Myogenesis

Postnatal myogenesis is a process of muscle tissue growth and generation that occurs after birth, typically following injury, infection, or prolonged physical activity. It begins with the activation of quiescent muscle stem cells, and ultimately leads to the formation of multinucleated myotubes and mature muscle fibers. Mitochondria play key roles during it, acting as metabolic hubs and signaling platforms. In this research, we showed the impact that mitochondrial stress-induced Integrated Stress Response (ISR) has on the postnatal myogenesis using the C2C12 mouse myoblast model. First, we performed a functional characterization of the model – confirming its capacity for proliferation, differentiation, as well as the efficient siRNA transfection. Second, we tested the pharmacological inhibitors of the electron transport chain – finding the most potent mitochondrial ISR activators in proliferation and differentiation conditions. Lastly, inducing the ISR and performing the immunostaining for specific differentiation markers, we clearly showed an impaired capacity for efficient differentiation under stress conditions. Furthermore, the knockdown of OMA1 –but not of LONP1- possessed the ability to suppress mitochondrial ISR activation. OMA1 is the very first component of the mitochondrial ISR pathway, and our preliminary results suggest that silencing it could selectively modulate ISR and block its activation.