Circadian Clock and Muscle Health

昼夜节律时钟和肌肉健康

基本信息

批准号：
10583484
负责人：
Karyn A Esser
金额：
$ 54.35万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583484
关键词：
3-Dimensional ARNTL gene Adult Aging Antibodies Attention Binding Bioluminescence ChIP-seq Chromatin Chronic Disease Coupled DNA Binding Data Dose Elements Exhibits Female Gene Expression Genes Genetic Genome Genomics Grant Health Knockout Mice Length Link Longevity Measures Messenger RNA Microfilaments Modeling Molecular Muscle Muscle Weakness Muscle function Muscular Atrophy Myopathy Outcome Output Pathology Phenotype Physiological Property Proteins RNA Splicing Regulation Role Sarcomeres Site Skeletal Muscle Structure Techniques Testing Thick Filament Tissues adeno-associated viral vector circadian pacemaker cofactor connectin epigenomics experimental study functional outcomes improved loss of function mutation male metabolomics mortality mouse model muscle strength programs promoter superresolution microscopy transcription factor transcriptome sequencing transcriptomics translational approach

项目摘要

We have shown that disruption of the muscle circadian clock mechanism through loss of the core clock gene, Bmal1, is sufficient to induce significant muscle weakness and surprisingly, increased mortality. Based on these findings, the overall objective of this grant is to pursue the fundamental understanding of the role of the muscle circadian clock in regulating a daily program of gene expression and how clock disruption leads to significant muscle weakness and diminished systemic health. We found that MyoD1 can modulate expression of the core clock gene, Bmal1 making it a bona fide tissue- specific circadian clock modifier1. We have also determined that MyoD1 and CLOCK:BMAL1 share peak binding at over 3000 sites across the muscle genome. These new findings provide support for our studies to define the mechanism(s) through which MyoD1 modulates the network properties of the clock mechanism as well as understanding the role of MyoD1 as a clock co-factor in the daily genomic and transcriptomic landscape in adult muscle. Downstream from MyoD1 and the clock factors, my lab has identified two muscle specific genes, Rbm20 and Tcap, that we propose link clock disruption with muscle weakness. Loss of muscle Bmal1, results in significant decreases in Rbm20 and Tcap expression and we find changes in sarcomere structure including variability of sarcomere length, distortions in M and Z lines and altered myofilament orientation. Lastly, the global Bmal1 knock out mouse, Bmal1KO, has been used as a model of advanced aging as it exhibits significant aging-like pathologies and has a median lifespan of 37wks. In preliminary experiments using this global Bmal1 KO mouse we rescued Bmal1 in skeletal muscles using an AAV vector with a muscle specific promoter. We found that this was sufficient to significantly improve muscle strength but also significantly extended lifespan. These are complementary to our findings of increased mortality with loss of muscle Bmal1 and demonstrate that rescuing Bmal1 only in skeletal muscle improves systemic health. In addition, with aging and many chronic diseases exhibiting muscle clock disruption, these results suggest that targeting the muscle clock mechanism holds potential as a translational strategy. We propose to test the following three specific aims: Specific Aim 1: To define the roles of MyoD1 within the core clock mechanism and as a co-factor for the daily transcriptomic landscape in skeletal muscle. Specific Aim 2: To test the clock controlled genes, Rbm20 and/or Tcap, for their roles in sarcomere structure and muscle function. Specific Aim 3: To determine the skeletal muscle specific changes required for improved lifespan in the Bmal1 KO mouse.

我们已经证明，核心时钟基因的丢失会破坏肌肉生物钟机制， Bmal1 足以引起明显的肌肉无力，并令人惊讶地增加死亡率。基于根据这些发现，这笔赠款的总体目标是寻求对肌肉生物钟在调节基因表达的日常程序中的作用以及生物钟破坏如何导致严重的肌肉无力和全身健康状况下降。我们发现 MyoD1 可以调节核心时钟基因 Bmal1 的表达，使其成为真正的组织 - 特定的生物钟调节剂1。我们还确定 MyoD1 和 CLOCK:BMAL1 共享峰值结合肌肉基因组的 3000 多个位点。这些新发现为我们的研究提供了支持将 MyoD1 调节时钟机制的网络属性的机制定义为以及了解 MyoD1 作为时钟辅助因子在日常基因组和转录组学中的作用成人肌肉的景观。在 MyoD1 和时钟因子的下游，我的实验室已经确定了两个肌肉特异性基因，Rbm20 和 Tcap，我们建议将时钟中断与肌肉无力联系起来。肌肉 Bmal1 的损失，导致显着 Rbm20 和 Tcap 表达减少，我们发现肌节结构发生变化，包括肌节长度、M 线和 Z 线扭曲以及肌丝方向改变。最后，全球Bmal1 敲除小鼠 Bmal1KO 已被用作晚期衰老模型，因为它表现出显着的衰老样特征病理，中位寿命为 37 周。在使用该全局 Bmal1 KO 的初步实验中在小鼠骨骼肌中，我们使用带有肌肉特异性启动子的 AAV 载体拯救了 Bmal1。我们发现这足以显着提高肌肉力量，同时也显着延长寿命。这些与我们关于肌肉 Bmal1 损失导致死亡率增加的发现相补充，并证明仅在骨骼肌中拯救 Bmal1 可以改善全身健康。此外，随着衰老和许多慢性病表现出肌肉时钟破坏的疾病，这些结果表明针对肌肉时钟机制具有作为转化策略的潜力。我们建议测试以下三个具体目标：具体目标 1：定义 MyoD1 在核心时钟机制中的作用，并作为日常的辅助因素骨骼肌中的转录组景观。具体目标 2：测试时钟控制基因 Rbm20 和/或 Tcap 在肌节结构中的作用和肌肉功能。具体目标 3：确定 Bmal1 延长寿命所需的骨骼肌具体变化 KO老鼠。