Mediators of Muscle Rejuvenation with Aging

项目摘要 组织功能随着年龄的增长而下降，这是可以通过锻炼来缓解的有害影响。这个 随年龄增长功能衰退的分子原因以及组织衰老可被缓解的程度 目前还不清楚运动情况。细胞向更年轻的表观遗传和表型年龄的逆转是由 山中因子(Oct3/4、SOX2、KLF4和MYC，或“OKSM”)。在骨骼肌中，体积最大的 在体内的组织中，MYC是运动诱导的唯一山中因子。MYC的反应也变得不那么迅速 随着年龄增长而锻炼。这项建议的目的是研究MYC在骨骼中所起的作用 肌肉在整个生命周期中的功能、代谢、细胞和分子可塑性。回答我们的研究 问题：我们开发了一种小鼠模型，允许对骨骼肌中的MYC进行搏动性控制 与肌肉纤维核(肌核)同时荧光标记的纤维用于提纯和下游 分析。我们还开发了一种新的老年小鼠自愿运动模型。我们将表演：1) 功能、生物能量和细胞分析，2)单个肌核RNA测序，3)全球DNA 每周搏动性MYC诱导和运动后肌核甲基化和甲基化时钟分析 在整个生命周期中。我们假设肌肉中MYC的诱导将模仿功能和细胞 运动适应贯穿一生的方方面面，并放大运动训练的效果。MYC将 在几个分子水平上调节年轻，包括由DNA甲基化决定的生物衰老 “时钟”时代。此外，我们假设在生命后期诱导MYC足以逆转分子和 肌肉老化的细胞方面。我们的实验将提供有关MYC在 骨骼肌及其在肌核中表观遗传和转录年龄逆转的能力。我们期待着 我们的创新方法和全面的假设驱动组学分析将作为基础 了解骨骼肌随年龄增长的质量调节，并为探索 调节运动的延缓衰老的效果。

Project Summary Tissue function declines with age which has deleterious effects that can be mitigated by exercise. The molecular causes of functional decline with age and the extent to which tissue aging can be mitigated by exercise is unclear. The reversal of cells to a younger epigenetic and phenotypic age is controlled by Yamanaka factors (OCT3/4, SOX2, KLF4, and MYC, or “OKSM”). In skeletal muscle, the most voluminous tissue in the body, MYC is the only Yamanaka factor induced by exercise. MYC also becomes less responsive to exercise with advancing age. The purpose of this proposal is to examine the role that MYC plays in skeletal muscle functional, metabolic, cellular, and molecular plasticity throughout the lifespan. To answer our research questions, we developed a mouse model that allows for pulsatile control of MYC specifically in skeletal muscle fibers simultaneous with fluorescent labeling of muscle fiber nuclei (myonuclei) for purification and downstream analyses. We also developed a novel murine model of voluntary exercise for aged mice. We will perform: 1) functional, bioenergetic, and cellular analyses, 2) single myonuclear RNA-sequencing, and 3) global DNA methylation and methylation clock analyses in myonuclei after weekly pulsatile MYC induction and exercise throughout the lifespan. We hypothesize that MYC induction in muscle will mimic functional and cellular aspects of exercise adaptation throughout the lifespan and amplify the effects of exercise training. MYC will mediate youthfulness at several molecular levels, including biological aging determined by DNA methylation “clock” age. Furthemore, we hypothesize that MYC induction late in life is sufficient to reverse molecular and cellular aspects of muscle aging. Our experiments will provide fundamental information on the role of MYC in skeletal muscle and its capacity for epigenetic and transcriptional age reversal in myonuclei. We expect that our innovative approaches and comprehensive hypothesis-driven -omics analyses will serve as a foundation for understanding skeletal muscle mass regulation with aging, and provide new directions for exploring what mediates the age-defying effects of exercise.