A Transient Wave of Cellular Senescence is Required for Myofiber Growth and Myonuclear Accretion Following Injury

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of proinflammatory factors known as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescent cells are “transiently” present within regenerating skeletal muscle and within the muscles of D2-mdx mice, a model of Muscular Dystrophy. Single-cell RNA sequencing revealed that macrophages and fibrogenic adipogenic progenitors are the primary senescent cell types following injury and upregulate known SASP factors and senescence pathway genes including Cdkn1a, Trp53 and Glb1. Importantly, treatment with ABT-263, a senolytic compound reduced the number of senescent cells, decreased muscle fiber size and impaired myonuclear accretion following injury. These results highlight the importance of “acute” senescence in facilitating muscle regeneration and suggest that senescent cells may have broad functions in tissue repair.