Aging reshapes injury-induced senescence into distinct stromal senotypes during muscle regeneration

Muscle regeneration is associated with transient induction of cellular senescence. However, whether this response represents a uniform program or distinct age-dependent senotypes remains unclear. Single-cell transcriptomic profiling revealed that injury-induced senescence-associated populations are extensively remodeled with aging, both in cellular composition and transcriptional identity. In aged regenerating muscle, the senescence-associated compartment showed increased representation of muscle stem cells (MuSCs)/myogenic progenitors, while C12FDG-positive fibro-adipogenic progenitors (FAPs) shifted toward an inflammatory and immune-associated state. By contrast, in young muscle, C12FDG-positive FAPs formed a major senescence-associated stromal population with a regeneration-associated program enriched for ECM remodeling, angiogenesis, and morphogenesis. Functionally, mice deficient in both Cdkn1a and Cdkn2a showed reduced senescence-associated responses and delayed muscle regeneration, while pharmacological targeting of Mcl-1 reduced senescence-associated stromal cells, suppressed regenerative FAP programs and impaired muscle repair. Mechanistically, senescence-enriched regenerative FAPs promoted myogenic differentiation through paracrine activity. Together, these findings identify injury-induced senescence as an age-remodeled and functionally heterogeneous response during muscle regeneration.