Murach Kevin A, Englund Davis A, Chambers Toby L, Dungan Cory M, Porter Hunter L, Wren Jonathan D, Freeman Willard M, Dupont-Versteegden Esther E, Wen Yuan
Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, USA.
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FASEB J. 2025 Mar 15;39(5):e70435. doi: 10.1096/fj.202500177R.
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.
卫星细胞在成年骨骼肌的单核细胞中占比很小。尽管它们相对稀少，但卫星细胞在肌肉适应中具有关键作用，尤其是在长期运动训练期间。卫星细胞在整个生命周期中介导骨骼肌对身体活动反应的机制仍在研究中，但表观遗传调控可能发挥作用。为了探究这种可能性，我们分析了雌性小鼠肌肉组织中的全基因组DNA甲基化模式，这些小鼠进行了有或没有卫星细胞参与的终身自愿无负重轮转运动。使用他莫昔芬诱导的Pax7-DTA模型在成年期消融卫星细胞。与久坐不动的小鼠相比，13个月的轮转运动仅在有卫星细胞的情况下，才会导致众多富含肌纤维的基因（Cacgn1、Dnm2、Mlip、Myl1、Myom2、Mstn、Sgca、Sgcg、Tnnc1、Tnni2、Tpm1和Ttn）启动子区域的肌肉DNA甲基化差异。这些基因与肌纤维特性、细胞结构、大小以及整体肌肉功能有关。对这些基因的表观遗传改变与之前在这些相同小鼠中观察到的卫星细胞耗竭后跑步适应性的组织学和体内损伤一致。与久坐不动的小鼠相比，只有在没有卫星细胞且进行终身跑步的情况下，Musk启动子区域的甲基化才会受到影响；这与表明卫星细胞影响骨骼肌神经支配的研究相吻合。确定卫星细胞在终身体育活动后对肌纤维身份基因的表观遗传效应，为这些罕见的干细胞如何在整个生命周期中促进肌肉适应和功能提供了新的方向。
