Myonuclear dynamics during skeletal muscle aging

项目概要/摘要 少肌症是一种破坏性的骨骼肌疾病，发生在高龄，由于各种慢性疾病 条件。尽管肌肉减少症广泛流行，但没有治疗选择，而且 这一过程背后的机制尚不完全清楚。骨骼肌衰老的主要标志 是肌纤维尺寸的减小，这可以通过单根肌纤维内的数百个肌核来控制。 肌核在发育过程中产生，成体时也可以通过细胞融合添加新的细胞核 肌肉干细胞（MuSC）。数百个原子核的存在以及添加更多原子核的需要引发了疑问 如果预先存在的肌核处于其转录上限，因此需要肌纤维添加新的核 用于适应。为了开始了解肌核维持肌肉大小的要求，我们生成了 独特的小鼠模型，允许滴定肌核数量并利用策略来跟踪特定的 肌核群体。我们最近的研究表明，肌核数量最终决定了肌核的大小 肌纤维，但肌核具有转录储备能力，可以增加生物合成的输出和 维持较大的细胞质体积。虽然核数量减少的小鼠的补偿性适应 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 损失，导致假设功能基因拷贝数的损失是肌肉减少症的一个原因。确实， 通过利用 snRNA-seq 技术，我们检测到小鼠衰老过程中肌核群体的变化，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 除了转录改变之外，基因拷贝数减少的另一种机制是肌核丢失 来自合胞体，并且未被 MuSC 融合体取代，并且众所周知，MuSC 在衰老过程中活性降低 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， 揭示衰老肌纤维的肌核中的转录储备，这是通过失调引起的 转录谱或肌核丢失，并阐明这种肌核不忠与 肌肉减少症的发展。具体来说，我们建议：1）了解分子和细胞后果 衰老过程中肌核数量减少的影响2）从分子角度剖析肌核的激活机制 发育和衰老过程中的肌核转录储备 3) 确定发育和衰老过程中肌核的周转是否 体内平衡、衰老和萎缩。成功完成这些研究将为我们提供独特的见解 肌肉减少症的肌核控制并提供新知识，以确定新的治疗策略 对抗肌肉损失。

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.