Cellular senescence in skeletal muscle aging: new mechanisms and therapeutic potential for sarcopenia [snMultiome_ATAC+GEX]

Skeletal muscle allows voluntary movement and plays a key role in regulating metabolism and homeostasis in the organism. Adult muscle stem cells, MuSCs, are responsible for muscle growth and regeneration. Skeletal muscle suffers from sarcopenia (muscle mass and function loss) during the aging process. Burgeoning evidence suggests that cellular senescence drives MuSC dysfunction in muscle aging. Activation of senescence-associated secretory phenotype (SASP) factors, which is one of the hallmarks of senescence, may be a driving mechanism of sarcopenia but no study so far has clearly defined cellular senescence atlas and SASP components in aging human muscles. Here in this study we propose to profile aging and senescence atlases in aging muscles using the state-of-art multiomics approaches. Our pilot results demonstrate the prevalence of cellular senescence and the dynamics/heterogeneity of SASPs in aging human muscle. Furthermore, regulators governing senescence state and SASP induction were defined. Moreover, we demonstrated the potential of senotherapeutic targeting for sarcopenia treatment. In the project we propose (1) To complete single cell multiomics mapping of aging muscle atlas. (2) To further elucidate cellular senescence in aging muscle. (3) To investigate JUNB regulation of MuSC SASP induction in aging muscle. (4) To test the potential use of senotherapeutics on aging muscle. Once completed, findings from this study will uncover novel knowledge of how MuSC senescence is involved in niche alteration and muscle aging through SASPs and demonstrate the possibility of developing senotherapeutics for treating sarcopenia.