Lipid droplet dynamics regulate adult muscle stem cell fate

The lipid droplet (LD) is a central hub for fatty acid metabolism in cells. Here we define the dynamics and explore the role of LDs in skeletal muscle satellite cells (SCs), a stem cell population responsible for muscle regeneration. In newly divided SCs, LDs are unequally distributed in sister cells exhibiting asymmetric cell fates, as the LDLow cell self-renews while the LDHigh cell commits to differentiation. When transplanted into regenerating muscles, LDLow cells outperform LDHigh cells in self-renewal and regeneration in vivo. Pharmacological inhibition of LD biogenesis or genetic inhibition of LD catabolism through knockout of Pnpla2 (encoding ATGL, the rate-limiting enzyme for lipolysis) disrupts cell fate homeostasis and impairs the regenerative capacity of SCs. Dysfunction of Pnpla2-null SCs is associated with energy insufficiency and oxidative stress that can be partially rescued by antioxidant (N-acetylcysteine) treatment. These results establish a direct link between LD dynamics and stem cell fate determination. [Display omitted] •LDs are highly dynamic during myogenic progression of satellite cells•Satellite cells with few LDs hold higher self-renewal capacity than those with many LDs•Inhibiting biogenesis or catabolism of LDs disrupts satellite cell fate homeostasis•Excessive accumulation of LDs leads to energy insufficiency and oxidative stress Yue et al. identify a role for lipid droplets (LDs) in fate determination and regeneration of satellite cells (SCs). LD distribution in newly divided SCs underlies cell fate, as LDLow cells self-renew while LDHigh cells commit to differentiation. Inhibiting LD biogenesis or catabolism alters SC fate and impairs regeneration.