Healthy somatic stem cell populations are important for tissue homeostasis, and accumulating mitochondrial dysfunction represents a source of damage against which stem cells must defend. Using a series of mouse models, we show that depletion of electron transport chain (ETC) function in murine muscle stem cells (MuSCs) depletes MuSC numbers and inhibits regeneration. Loss of ETC function triggers MuSCs to bypass activation and directly fuse with neighboring myofibers in a reactive oxygen species-dependent manner, via reogranization of actin network. Inhibition of MuSC-myofiber fusion allows damaged MuSCs to regenerate dysfunctional myofibers. Intriguingly, the contribution of damaged MuSCs to existing myofibers is sufficient to initiate myopathy. Thus, existing myofibers act as a cellular “sponge” for damaged MuSCs, a novel mechanism where maintenance of MuSC health is balanced by accumulating tissue damage.