Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21 cip1 -driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.
Skeletal muscle mass and function can decline with aging, resulting in a syndrome known as sarcopenia. This decline is linked to functional alterations in critical cell types within mature muscle, including fibro-adipogenic progenitors (FAPs) and satellite cells (SCs), driven in part by cellular senescence. We utilized single-cell RNA sequencing and isolated FAPs and SCs to identify novel targets responsible for senescent cell killing - senolysis. We identified the small alpha-crystalline heat shock protein CRYAB as a novel senolytic target. Using chemical inhibitor screening of CRYAB, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic capable of killing senescent cells. We validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential new class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.
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