Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling [CUT&Run]
Sarcopenia, the age-related decline in muscle mass, strength, and function, is characterized by impaired muscle homeostasis, reduced regenerative potential of muscle stem cells (MuSCs), and increased fibrosis. Here, we report that aged MuSCs can autonomously instruct fibro-adipogenic progenitors (FAPs) to proliferate and acquire a fibrogenic phenotype, independent of other cell types. Both the Polycomb-deficient Ezh2-/- mouse model and aged mice exhibited defective regeneration, FAP expansion, fibrosis, and elevated secretion of interleukin 6 (IL-6) and Spp1/Osteopontin by MuSCs. In aged MuSCs, reduction of the histone H3K27me3 repressive mark at the Nfbk1 gene correlated with its increased expression, enhanced chromatin recruitment to the IL6 and Spp1 genes, leading to their activation. Pharmacological inhibition of IL-6 and Spp1 signaling in co-culture systems or in aged mice reduced FAP proliferation and muscle fibrosis. These findings indicate that epigenetic dysregulation of aged MuSCs contributes to aged-related muscle fibrosis. Overall design: To investigate the mechanism underlying the increased activation of IL-6 and Spp1 signaling in aged MuSCs, we compared genomewide distribution of the epiegenetic repressive mark H3K27me3 in adult and aged MuSCs by CUT&RUN.