Characterization of cellular senescence in aging skeletal muscle

Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single-cell and bulk RNA sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16(Ink4a) together with multiple senescence-related genes and concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p21(Cip1). Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging. Senescent cells accumulate with age and contribute to the functional decline of many tissues; however, their role in skeletal muscle is not well understood. Here the authors comprehensively assess cellular senescence in skeletal muscle of young and old mice and detail senescence features in subpopulations of p16(+) fibroadipogenic progenitors and p21(+) myofibers.

Automated summary

This study comprehensively assesses cellular senescence in skeletal muscle of young and old mice using single-cell and bulk RNA sequencing, as well as imaging methods. The results demonstrate that a subpopulation of fibroadipogenic progenitors in old mice highly express p16(Ink4a) and multiple senescence-related genes, accompanied by DNA damage and chromatin reorganization. A senescence phenotype is also observed in isolated myofibers, governed by p21(Cip1). Treatment with a senotherapeutic intervention improves age-related molecular and morphological changes and enhances skeletal muscle strength in old mice. Furthermore, the senescence phenotype is conserved in skeletal muscle from older humans.