Senescence as a regulatory mechanism in skeletal muscle repair in young mice

Senescence is broadly considered an age-related phenomenon; however, it also been implicated in normal tissue repair and wound healing. Skeletal muscle repair is a complex process that requires the coordination of several different cell populations but the role of senescence in skeletal muscle repair has yet to be fully elucidated. We hypothesize that senescence serves as a control mechanism throughout the regenerative process and the removal of senescent cells through senolytics will negatively impact the repair process in young mice. Briefly, young mice were exposed to either (a) vehicle (VEH), receiving only a cardiotoxin (CTx) injection in one hindlimb or (b) 7 days of senolytic treatment (SEN) pre-CTx and 3x/week for 4 weeks post-CTx. Dasatinib + Quercetin (D+Q) was used to selectively eliminate senescent cells. There were no significant differences between groups in functional measures such as hindlimb grip strength and cross-sectional area. eMHC+ fibers remained elevated at D28 in the SEN group. Macrophage infiltration was twice as high in the SEN group compared to VEH at D7. Satellite cell quantity and fibrotic area were significantly increased at D14 in the SEN group compared to VEH. We conclude that reducing senescent cells during muscle repair in young mice significantly altered the kinetics of muscle repair. Therefore, senescent cells may act as a regulatory mechanism in skeletal muscle to orchestrate the activity of the different cell populations involved in repair and regeneration such as immune cells, satellite cells, and fibrotic cells.