(For a full list see below)
Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and tightly regulated by macrophages (MPs) and fibroadipogenic progenitors (FAPs) in their niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophicmuscle. Here we demonstrate intrinsic deletion of transcription factor Yin Yang 1 (YY1) in MuSCs exacerbates dystrophic pathologies by altering composition and heterogeneity of MPs and FAPs. Further analysis reveals YY1 loss induces expression of immune genes in MuSCs, including C-C motif chemokine ligand 5 (Ccl5). Augmented CCL5 secretion promotes MP recruitment via CCL5/C-C chemokine receptor 5 (CCR5) crosstalk, which subsequently hinders FAP clearance through elevated Transforming growth factor-β1 (TGFβ1). Maraviroc-mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we demonstrate YY1 represses Ccl5 transcription by binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study demonstrates the critical role of MuSCs in actively shaping their niche and provides novel insight into the therapeutic intervention of muscle dystrophy.
Yang Li*, Chuhan Li, Qiang Sun, Xingyuan Liu, Fengyuan Chen, Yeelo Cheung, Yu Zhao, Ting Xie, Bénédicte Chazaud, HaoSun, Huating Wang
Nature Communications, 2025, DOI: 10.1038/s41467-025-56474-w
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 inmononucleated cells of human skeletalmuscle and provide the first senescence atlas. We demonstrate the intra- and interpopulational 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 ageassociated 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.
Yang Li*, Chuhan Li, Qin Zhou, Xingyuan Liu, Yulong Qiao, Ting Xie, Hao Sun, Michael Tim-Yun Ong, Huating Wang
Nature Communications, 2025, DOI: 10.1038/s41467-025-61403-y