Cicciarello, D.; Mouradian, S.; Pitchecanin, M.; Jarassier, W.; Kneppers, A.; Mounier, R.; Schaeffer, L.; Scionti, I.

Lipid metabolism is a key process required for muscle stem cell (MuSCs) function during regenerative myogenesis. However, the molecular pathway responsible of such regulation is still unknown. Studies of lysine demethylase PHF2 have reported its critical role in lipid metabolism in pathological processes, although there are no data regarding its role during MuSC fate transition. Here we show that PHF2 controls lipid droplet homeostasis in MuSCs during regenerative myogenesis, by promoting the contact between lipid droplets and mitochondria. Consistently, in absence of PHF2, myocytes accumulate lipid droplets, leading to mitochondrial dysfunction and impaired regeneration. Interestingly, such phenotype is rescued by AMPKa2-PHF2 phospho-mimetic mutant expression. Our findings provide evidence that PHF2 is part of AMPKa2 signaling and underscore the critical role of AMPKa2/PHF2 axis in regulating lipid droplets homeostasis during MuSC fate.