Differentiation reveals latent features of aging and an energy barrier in murine myogenesis

Skeletal muscle experiences a decline in lean mass and regenerative potential with age, in part due to intrinsic changes in progenitor cells. However, it remains unclear how age-related changes in progenitors manifest across a differentiation trajectory. Here, we perform single-cell RNA sequencing (RNA-seq) on muscle mononuclear cells from young and aged mice and profile muscle stem cells (MuSCs) and fibro-adipose progenitors (FAPs) after differentiation. Differentiation increases the magnitude of age-related change in MuSCs and FAPs, but it also masks a subset of age-related changes present in progenitors. Using a dynamical systems approach and RNA velocity, we find that aged MuSCs follow the same differentiation trajectory as young cells but stall in differentiation near a commitment decision. Our results suggest that differentiation reveals latent features of aging and that fate commitment decisions are delayed in aged myogenic cells in vitro.