A satellite cell-dependent epigenetic fingerprint in skeletal muscle identity genes after lifelong physical activity

Satellite cells comprise a small proportion of mononuclear cells in adult skeletal muscle. Despite their relative rarity, satellite cells have critical functions in muscle adaptation, particularly during prolonged exercise training. The mechanisms by which satellite cells mediate skeletal muscle responsiveness to physical activity throughout the lifespan are still being defined, but epigenetic regulation may play a role. To explore this possibility, we analyzed global DNA methylation patterns in muscle tissue from female mice that engaged in lifelong voluntary unweighted wheel running with or without satellite cells. Satellite cells were ablated in adulthood using the tamoxifen-inducible Pax7-DTA model. Compared to sedentary mice, wheel running for 13 months caused muscle DNA methylation differences in the promoter regions of numerous muscle fiber-enriched genes—Cacgn1, Dnm2, Mlip, Myl1, Myom2, Mstn, Sgca, Sgcg, Tnnc1, Tnni2, Tpm1, and Ttn—only when satellite cells were present. These genes relate to muscle fiber identity, cytoarchitecture, and size as well as overall muscle function. Epigenetic alterations to such genes are consistent with previously observed histological and in vivo impairments to running adaptation after satellite cell depletion in these same mice. Musk promoter region methylation was affected only in the absence of satellite cells with lifelong running relative to sedentary; this dovetails with work showing that satellite cells influence skeletal muscle innervation. Defining the epigenetic effects of satellite cells on identity genes in muscle fibers after lifelong physical activity provides new directions for how these rare stem cells can promote muscle adaptation and function throughout the lifespan.