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.

项目摘要组织功能随着年龄的增长而下降，这已经删除了可以通过运动来缓解的效果。这分子原因是随着年龄的增长而功能下降的原因，以及组织衰老的程度可以通过运动不清楚。细胞向年轻的表观遗传和表型年龄的逆转受到控制 Yamanaka因素（Oct3/4，Sox2，KLF4和MYC或“ OKSM”）。在骨骼肌肉中，最庞大 MYC是体内的组织，是运动引起的唯一Yamanaka因子。 MYC也变得不太反应迅速随着年龄的增长而运动。该提议的目的是检查MYC在骨骼中的作用整个生命周期中的肌肉功能，代谢，细胞和分子可塑性。回答我们的研究问题，我们开发了一种鼠标模型，该模型允许在骨骼肌肉中专门对MYC进行脉动控制纤维与肌肉纤维核（肌酸）的荧光标记同时进行纯化和下游分析。我们还为老年小鼠开发了一种新型的自愿运动鼠模型。我们将表演：1）功能性，生物能和细胞分析，2）单核RNA测序和3）全局DNA 每周脉冲MYC诱导和运动后，在肌核中进行甲基化和甲基化时钟分析在整个生命周期中。我们假设肌肉中的MYC诱导会模仿功能和细胞在整个生命周期中进行运动适应的各个方面，并扩大运动训练的影响。妈会介导几个分子水平的年轻性，包括由DNA甲基化确定的生物老化 “时钟”年龄。此外，我们假设生命后期的MYC诱导足以逆转分子和肌肉衰老的细胞方面。我们的实验将提供有关MYC在骨骼肌及其表观遗传和转录年龄逆转的能力。我们期望这一点我们的创新方法和全面的假设驱动的 - 组合分析将成为基础用于了解骨骼肌肉质量调节，并提供新的方向来探索什么介导锻炼年龄的影响。