Muscle injury induces a transient senescence‐like state that is required for myofiber growth during muscle regeneration

Abstract 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 pro‐inflammatory factors known as the senescence‐associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single‐cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are “transiently” present within regenerating skeletal muscle and within the muscles of D2‐ mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibrog–adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence‐associated beta‐gal (SA‐β‐gal) activity. Importantly, when these cells were removed with ABT‐263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion. These results highlight that an “acute” senescent phenotype facilitates regeneration similar to skin and neonatal myocardium.