Circadian Clock and Muscle Health

昼夜节律时钟和肌肉健康

• 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
• 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

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，肌肉生物钟机制的破坏是由于核心生物钟基因的缺失，