Mediators of Muscle Rejuvenation with Aging

肌肉再生与衰老的调节剂

基本信息

批准号：
10734927
负责人：
Kevin Murach
金额：
$ 49.24万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734927
关键词：
Acute Adult Affect Age Age Months Aging Bioenergetics Biological Biological Aging Cell Nucleus Cells Characteristics DNA DNA Methylation DNA Methylation Regulation Dose Doxycycline Elderly Epigenetic Process Euthanasia Exercise Extracellular Matrix Female Fiber Foundations Gastrocnemius Muscle Gene Expression Genetic Transcription Genome Health Hindlimb Histologic Human In Vitro Knowledge Label Life Life Expectancy Longevity Measures Mediating Mediator Metabolic Methylation Modeling Molecular Mus Muscle Muscle Fibers Muscle function Muscle satellite cell Myosin ATPase Nuclear Periodicals Phenotype Physical Function Physiologic pulse Plantaris muscle Play Population Process Regulation Rejuvenation Reporting Research Resistance Resolution Role Running Shapes Skeletal Muscle Soleus Muscle Spirometry Stimulus Testing Time Tissues age effect aged c-myc Genes cost endurance exercise enhancing factor epigenome exercise training experimental study functional decline functional mimics genome wide methylation healthspan improved in vivo injury recovery innovation male methylation pattern methylome mouse model muscle aging muscle form novel overexpression resistance exercise sedentary senescence transcriptome transcriptome sequencing

项目摘要

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.

项目概要组织功能随着年龄的增长而下降，这会产生有害影响，但可以通过锻炼来减轻。随着年龄的增长功能衰退的分子原因以及可以通过以下方式减轻组织衰老的程度运动向年轻表观遗传和表型年龄的逆转尚不清楚。山中因子（OCT3/4、SOX2、KLF4 和 MYC，或“OKSM”）在骨骼肌中体积最大。在体内组织中，MYC 是唯一由运动引起的山中因子，MYC 也会变得反应迟钝。随着年龄的增长进行锻炼该提案的目的是检查 MYC 在骨骼中所扮演的角色。肌肉在整个生命周期中的功能、代谢、细胞和分子可塑性来回答我们的研究。为了解决这些问题，我们开发了一种小鼠模型，可以对骨骼肌中的 MYC 进行脉动控制纤维同时对肌纤维核（肌核）进行荧光标记，用于纯化和下游我们还开发了一种针对老年小鼠的新型自愿运动模型，我们将进行：1）。功能、生物能和细胞分析，2) 单肌核 RNA 测序，以及 3) 整体 DNA 每周脉动 MYC 诱导和运动后肌核的甲基化和甲基化时钟分析我们勇敢地说，肌肉中的 MYC 诱导将模仿功能和细胞。 MYC 将影响整个生命周期的运动适应各个方面，并增强运动训练的效果。在多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此外，我们认为晚年的 MYC 诱导足以逆转分子和年龄。我们的实验将提供有关 MYC 在肌肉衰老中的作用的基本信息。骨骼肌及其在肌核中表观遗传和转录年龄逆转的能力。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，并为探索什么提供新方向调节运动的抗衰老作用。