Myonuclear dynamics during skeletal muscle aging

项目概要/摘要 肌肉减少症是一种毁灭性的骨骼肌状况，发生在老年人和由于各种慢性 条件尽管肌肉减少症广泛流行，但没有治疗选择， 这一过程的基本机制尚未完全了解。骨骼肌老化的主要标志 是肌纤维尺寸的减小，这可以通过单个肌纤维内的数百个肌核来控制。 肌核在发育过程中不断积累，在成体中通过细胞融合也可产生新的细胞核 肌肉干细胞（MuSC）数百个原子核的存在以及需要添加更多的原子核引发了一些问题 如果预先存在的肌核处于它们的转录上限并因此需要肌纤维添加新的核 来适应。为了开始了解肌核维持肌肉大小的需要，我们生成了一个 独特的小鼠模型，允许滴定肌球蛋白的数量，并利用策略来跟踪特定的 Mycobacterium populations.我们最近的研究表明，肌肉的数量最终决定了肌肉的大小。 肌纤维，但肌核具有转录储备能力，以增加生物合成输出， 维持较大的细胞质体积。而细胞核数目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生长的证据有关。 这导致了功能基因拷贝数的丢失是肌肉减少症的贡献者的假设。的确， 通过利用snRNA-seq技术，我们检测到在小鼠衰老过程中， 转录失调，这可能是解释基因拷贝数减少的一种机制。在 除了转录改变外，基因拷贝数减少的另一个机制是肌核丢失 并且不被MuSC融合所取代，并且已知MuSC在老年人中具有降低的活性。 肌肉.根据这些初步数据，我们将利用独特的模型和Mycobacteria跟踪系统， 揭示了衰老肌纤维肌核中的转录储备， 转录谱或肌萎缩症的损失，并阐明这种肌萎缩症的不忠和之间的联系， 肌肉减少症的发展。具体来说，我们建议：1）了解分子和细胞的后果 2）从分子上剖析了衰老过程中肌纤维数量减少的激活机制， 3）确定发育和衰老过程中肌核的转录储备， 体内平衡老化和萎缩成功完成这些研究将提供独特的见解， 肌萎缩症的控制，并提供新的知识，将确定新的治疗策略， 对抗肌肉萎缩

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.