Muscle stem cell renewal suppressed by Gas1 can be reversed by GDNF in mice

Muscle undergoes progressive weakening and regenerative dysfunction with age due in part to the functional decline of skeletal muscle stem cells (MuSCs). MuSCs are heterogeneous but whether their gene expression changes with age and the implication of such changes are unclear. Here we show that in mice, Growth arrest-specific gene 1 (Gas1) is expressed in a small subset of young MuSCs with its expression progressively increasing in larger fractions of MuSCs later in life. Over-expression of Gas1 in young MuSCs and inactivation of Gas1 in aged MuSCs support that Gas1 reduces the quiescence and self-renewal capacity of MuSCs. Gas1 reduces Ret signaling, which is required for MuSC quiescence and self-renewal. Indeed, we show that the Ret ligand, Glial Cell-Derived Neurotrophic Factor (GDNF), can counteract Gas1 by stimulating Ret signaling and enhancing MuSC self-renewal and regeneration, thus improving muscle function. We propose that strategies aimed to target this pathway can be exploited to improve the regenerative decline of muscle stem cells.