Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia

Abstract

Cellular senescence is a hallmark of organismal aging but how it drives aging in human tissues is not fully understood. Here we leverage single nucleus multiomics to profile senescence in mononucleated cells of human skeletal muscle and provide the first senescence atlas. We demonstrate the intra- and inter-populational transcriptomic and epigenomic heterogeneity and dynamics of cellular senescence. We also identify commonalities and variations in senescence-associated secretory phenotypes (SASPs) among the cells and elucidate SASP mediated cellular interactions and niche deregulation. Furthermore, we identify targetable SASPs and demonstrate the possibility of using Maraviroc as a pharmacological senotherapeutic for treating age-associated sarcopenia. Lastly, we define transcription factors that govern senescence state and SASP induction in aging muscle and elucidate the key function and mechanism of JUNB in SASP activation. Altogether, our findings demonstrate the prevalence and function of cellular senescence in skeletal muscle and identify a novel pharmacological intervention for sarcopenia.