Mediators of Muscle Rejuvenation with Aging

项目摘要 组织功能随着年龄的增长而下降，这具有可以通过运动减轻的有害影响。的 随着年龄的增长，功能下降的分子原因以及组织老化可以通过以下方式减轻的程度 演习不清楚。细胞向更年轻的表观遗传和表型年龄的逆转由以下因素控制： Yamanaka因子（OCT 3/4、SOX 2、KLF 4和MYC或"OKSM"）。在骨骼肌中， 在体内的组织中，MYC是唯一由运动引起的Yamanaka因子。MYC也变得不那么敏感 随着年龄的增长而锻炼。本提案的目的是审查MYC在骨骼 肌肉功能、代谢、细胞和分子可塑性贯穿整个生命周期。为了回答我们的研究 问题，我们开发了一种小鼠模型，允许专门在骨骼肌中脉动控制MYC 纤维，同时荧光标记肌纤维核（肌核）用于纯化和下游 分析。我们还开发了一种新的老年小鼠自愿运动模型。我们将执行：1） 功能、生物能量和细胞分析，2）单个mycoplasma RNA测序，和3）整体DNA 每周脉冲MYC诱导和运动后肌核中的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的诱导将模拟功能和细胞 在整个生命周期的运动适应方面，并扩大运动训练的效果。MYC将 在几个分子水平上介导年轻化，包括由DNA甲基化决定的生物衰老 "时钟"年龄。此外，我们假设MYC诱导在生命后期足以逆转分子和 肌肉老化的细胞方面。我们的实验将提供关于MYC在以下方面的作用的基本信息： 骨骼肌及其在肌核中表观遗传和转录年龄逆转能力。我们预计 我们的创新方法和全面的假设驱动组学分析将作为基础 了解骨骼肌质量随衰老的调节，并为探索 调节锻炼的抗衰老效应。

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.