The Integrated Stress Response Pathway Improves Aged Murine Muscle Stem Cell Activation and in vivo Regeneration

For efficient regeneration, muscle stem cells (MuSCs) transition out of quiescence through a series of progressively more activated states. During MuSC aging, transition through the earliest steps is the slowest and delayed, with the molecular regulators that govern this transition not well characterized. Here, we found that aged MuSCs have increased baseline integrative stress response (ISR) activity in quiescence that does not increase during activation to levels observed in adult MuSCs. Rapid and transient pharmacological ISR activation in vitro was sufficient to increase aged MuSC activation rate through ISR-activator (ISR-a) and migratory behavior and also alter the transcriptional states toward an adult phenotype. ISR activation also improved aged MuSC potency and aged mouse muscle regeneration in vivo. Therefore, pharmacological activation of the ISR has therapeutic potential to improve MuSC function and skeletal muscle repair during aging.