Differentiation reveals the plasticity of age-related change in murine muscle progenitors

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 if age-related changes in progenitors persist across a differentiation trajectory or if new age-related changes manifest in differentiated cells. To investigate this possibility, we performed single cell RNA-seq on muscle mononuclear cells from young and aged mice and profiled muscle stem cells (MuSCs) and fibro/adipose progenitors (FAPs) after differentiation. Differentiation increased the magnitude of age-related change in MuSCs and FAPs, but also masked a subset of age-related changes present in progenitors. Using a dynamical systems approach and RNA velocity, we found that aged MuSCs follow the same differentiation trajectory as young cells, but stall in differentiation near a commitment decision. Our results suggest that age-related changes are plastic across differentiation trajectories and that fate commitment decisions are delayed in aged myogenic cells.