Single-cell transcriptomic analysis of skeletal muscle regeneration across mouse lifespan identifies altered progenitor cell states associated with senescence
Skeletal muscle regeneration is driven by the interaction of myogenic and non-myogenic cells. In aging, regeneration is impaired due to various dysfunctions of myogenic and non-myogenic cells, but this is not understood comprehensively. We collected an integrated atlas of 273,923 single-cell transcriptomes from muscles of young, old, and geriatric mice (4, 20, 26 months-old) at six time-points following myotoxin injury. We identified eight cell types, including T and NK cells and multiple macrophage subtypes that displayed accelerated or delayed dynamics between ages. Through pseudotime analysis, we observed myogenic cell states and trajectories specific to old and geriatric ages. To explain these age differences, we assessed cellular senescence by scoring experimentally derived and curated gene-lists, which pinpointed stalled senescent-like subsets specifically within the self-renewing muscle stem cells as elevated in older muscles. This resource provides a holistic portrait of the altered cellular states underlying skeletal muscle regeneration decline across mouse lifespan. Overall design: Single-cell RNA-seq datasets for uninjured and notexin-injured mouse tibialis anterior muscles. Muscles were collected at six time points (0, 1, 2, 3.5, 5, and 7 days) and there are 4 replicates per time point.