Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence

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.

Automated summary

The study reveals that muscle aging is associated with various factors such as inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons. Transcriptome profiling identifies changes in gene expression related to age and frailty, including key genes like MYH8, PDK4, and IGFN1. Additionally, a subpopulation expressing CDKN1A in aged samples suggests cellular senescence driven by p21(cip1). These findings provide valuable insights into age-related muscle loss and can guide the development of therapeutic strategies.