Myonuclear dynamics during skeletal muscle aging

骨骼肌衰老过程中的肌核动力学

• 批准号: 10714194
• 负责人: Douglas Paul Millay
• 金额: $ 42.34万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714194
• 关键词: Acceleration; Accounting; Adult; Aging; Atrophic; Biological Phenomena; Breathing; Cell Nucleus; Cell Size; Cell fusion; Cells; Chronic; Compensation; Cytoplasm; Data; Development; Elderly; Exhibits; Gene Dosage; Gene Expression Profile; Genetic; Genetic Transcription; Giant Cells; Goals; Growth; Health; Homeostasis; Knowledge; Link; Longevity; Maintenance; Metabolism; Modeling; Molecular; Morphology; Movement; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Atrophy; Nuclear; Output; Physiological; Population; Prevalence; Process; Regulation; Role; Skeletal Muscle; System; Technology; Testing; Titrations; Transcriptional Activation; Transcriptional Regulation; aged; combat; functional loss; insight; mouse model; multiple omics; muscle aging; muscle form; novel; novel therapeutic intervention; precursor cell; premature; preservation; resilience; sarcopenia; satellite cell; senescence; single nucleus RNA-sequencing; skeletal; skeletal muscle wasting; tool

Project Summary/Abstract Sarcopenia is a devastating skeletal muscle condition that occurs in advanced age and due to various chronic conditions. Despite the widespread prevalence of sarcopenia there are no treatment options and the mechanisms underlying this process are not completely understood. A major hallmark of skeletal muscle aging is a reduction in myofiber size, which can be controlled by the hundreds of myonuclei within a single myofiber. Myonuclei are accrued during development, and new nuclei can also be added in the adult through cellular fusion of muscle stem cells (MuSCs). The presence of hundreds of nuclei and the need to add more has led to questions if the pre-existing myonuclei are at their transcriptional ceiling and thus require the myofiber to add new nuclei for adaptations. To begin to understand the requirement for myonuclei to maintain muscle size, we generated a unique mouse model that allows titration of myonuclear numbers and utilized strategies to track specific myonuclear populations. Our recent studies showed that myonuclear numbers ultimately determine size of myofibers, but that myonuclei possess a transcriptional reserve capacity to increase biosynthetic output and maintain larger cytoplasmic volumes. While the compensatory adaptations in mice with reduced nuclear numbers were advantageous during development, they were associated with evidence of accelerated aging and muscle loss, leading to the hypothesis that loss of functional gene copy numbers is a contributor to sarcopenia. Indeed, by utilizing snRNA-seq technology, we detected altered myonuclear populations during mouse aging suggesting dysregulated transcription, which could be one mechanism to explain a reduction in gene copy numbers. In addition to altered transcription, another mechanism for reductions of gene copy numbers is if myonuclei are lost from the syncytium and not replaced by MuSC fusion, and it is known that MuSCs have reduced activity in aged muscle. Based on these preliminary data, we will utilize unique models and myonuclear tracking systems, to uncover the transcriptional reserve in myonuclei of aging myofibers, elicited either through dysregulated transcriptional profiles or myonuclear loss, and elucidate the link between such myonuclear infidelity and the development of sarcopenia. Specifically, we propose to: 1) understand the molecular and cellular consequences of reductions in myonuclear number during aging 2) molecularly dissect the mechanisms of activation of myonuclear transcriptional reserve during development and aging 3) determine if myonuclei turnover during homeostasis, aging, and atrophy. Successful completion of these studies will provide unique insight into the myonuclear control of sarcopenia and provide new knowledge that will identify new therapeutic strategies to combat muscle loss.

项目摘要/摘要 骨质疏松症是一种毁灭性的骨骼肌疾病，发生在中老年，由各种慢性疾病引起 条件。尽管石棺减少症普遍流行，但没有治疗选择，而且 这一过程背后的机制还没有完全被理解。骨骼肌衰老的一个主要标志 是肌纤维尺寸的减小，这可以由单个肌纤维中的数百个肌核来控制。 肌核在发育过程中积累，也可以通过细胞融合在成人体内增加新的核。 肌肉干细胞(MuSC)。成百上千个原子核的存在以及增加更多原子核的需要引发了人们的疑问 如果先前存在的肌核处于转录上限，因此需要肌纤维添加新的核 用于改编。为了开始理解肌核维持肌肉大小的要求，我们生成了一个 独特的小鼠模型，允许滴定肌核数量并利用策略跟踪特定的 肌核种群。我们最近的研究表明，肌核数量最终决定了 肌纤维，但肌核具有转录储备能力，以增加生物合成产量和 保持较大的细胞质体积。而核数减少的小鼠的代偿性适应 在发育过程中是有利的，它们与加速衰老和肌肉的证据有关 丢失，导致假设功能基因拷贝数丢失是导致石棺减少的原因之一。的确， 利用SnRNA-seq技术，我们检测到小鼠衰老过程中肌核数量的变化，这表明 转录失调，这可能是解释基因拷贝数减少的一种机制。在……里面 除了转录改变外，基因拷贝数减少的另一种机制是肌核丢失 来自合胞体，不被MUSC融合所取代，已知MUSCs在老年人中活性降低 肌肉。基于这些初步数据，我们将利用独特的模型和肌核跟踪系统， 发现衰老的肌纤维在肌核中的转录储备，这种转录储备是由调控失调引起的 转录谱或肌核丢失，并阐明这种肌核不忠与 骨质疏松症的发展。具体地说，我们建议：1)理解分子和细胞的后果 在衰老过程中肌核数量的减少2)从分子上剖析了肌细胞活化的机制 发育和衰老过程中的肌核转录储备决定了肌核在发育和衰老过程中的周转 动态平衡、衰老和萎缩。这些研究的成功完成将为我们提供独特的见解 肌核控制石棺减少症，并提供新的知识，将确定新的治疗策略 战斗中的肌肉损失。