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 肌肉减少症是一种毁灭性的骨骼肌状况，发生在高龄，并且由于各种慢性 状况。尽管肌肉减少症的普遍普遍存在，但没有治疗选择 该过程的基础机制尚未完全理解。骨骼肌老化的主要标志 是肌纤维尺寸的减小，可以在单个肌纤维中受到数百个肌核的控制。 在发育过程中，肌核脂是在成年人通过细胞融合中添加的新核的 肌肉干细胞（MUSC）。数百个核的存在以及增加更多的核心导致了问题 如果预先存在的肌核在其转录天花板处，因此需要肌纤维添加新的核 适应。为了开始了解肌核对保持肌肉大小的要求，我们产生了一个 独特的鼠标模型，允许滴定肌核数字并利用策略来跟踪特定 肌核种群。我们最近的研究表明，肌核数最终确定 肌纤维，但肌核具有转录储备的能力，可以增加生物合成产量和 保持较大的细胞质体积。而小鼠的补偿性适应性减少了 在开发过程中是有利的，它们与加速衰老和肌肉的证据有关 损失，导致假设，即功能基因拷贝数的丧失是肌肉减少症的原因。的确， 通过利用SNRNA-Seq技术，我们在鼠标衰老过程中检测到了肌核群体的改变 转录失调，这可能是解释基因拷贝数减少的一种机制。在 除了转录的改变，基因拷贝数减少的另一种机制是造成肌核 从合成剂中，不被MUSC融合所取代，众所周知，MUSC的活性降低了 肌肉。基于这些初步数据，我们将利用唯一的模型和肌核跟踪系统， 发现肌纤维衰老的肌核中的转录储备，通过失调而引起 转录曲线或肌核损失，并阐明这种肌核不忠与 肌肉减少症的发展。具体而言，我们建议：1）了解分子和细胞后果 衰老期间肌能数量的减少2）分子剖析激活机制 开发和衰老期间的肌核转录储备 稳态，衰老和萎缩。这些研究的成功完成将为您提供独特的见解 肌肉减少症的肌能控制，并提供新的知识，以确定新的治疗策略 战斗肌肉损失。