Link to HAL – pasteur-05124677
Link to DOI – 10.1101/2023.12.12.571148
2025
Muscle regeneration is associated with transient induction of cellular senescence. However, the role of senescence in muscle regeneration of young mice remains unclear. Using a mouse model deficient in both Cdkn1a and Cdkn2a, we find that a marked reduction in senescent cells correlates with delayed muscle regeneration. Single-cell RNA sequencing reveals a heterogeneous senescence program composing of multiple cell types. Notably, senescent fibro-adipogenic progenitors (FAPs) upregulate Mcl-1 to acquire apoptosis resistance. Moreover, removing senescent FAPs using a Mcl-1 inhibitor S63845 impairs muscle regeneration. Furthermore, we find that senescent FAPs promotes myogenic differentiation in a paracrine manner. Hence, these results highlight the beneficial role of senescent stromal cells in supporting muscle regeneration.