Identifying the Structural Adaptations that Drive the Mechanically Induced Growth of Skeletal Muscle

项目摘要/摘要 机械信号在骨骼肌群的调节和肌肉的维持中起着重要作用 群众对疾病预防和生活质量有很大贡献。尽管机械设备之间的联系 信号和肌肉质量的调节已经被认识到几十年了，控制这一过程的机制 流程仍然定义不清。例如，大多数研究表明，机械诱导的骨骼生长 肌肉是由现有肌纤维大小的增加而不是由数量的增加驱动的 肌纤维。此外，目前的模型断言，肌纤维尺寸的增加是由 蛋白质合成速率和蛋白质降解速率之间的平衡，这反过来又会导致堆积 新合成的蛋白质(NSP)和伴随的驱动生长反应的结构变化。 例如，众所周知，机械载荷的增加会导致微观结构的变化 作为肌纤维的径向生长。然而，令人惊讶的是，推动这些变化的超微结构适应 微观结构的变化还没有定义。事实上，一些基础性的重要问题，如 肌纤维的径向生长是否是由肌原纤维的尺寸和/或数量的增加 无人接听。同样，在机械诱导生长过程中NSP积累的位置(S) (即生长的地点)是未知的。因此，该项目的主要目标之一是填补这些空白 知识。另一个主要目标是更好地了解控制 机械诱导生长的不同方面。例如，我们之前的工作已经建立了信号 通过mTORC1在机械刺激诱导细胞径向生长的过程中发挥核心作用 肌纤维。然而，我们的初步数据表明，肌纤维的纵向生长也可以使 对机械诱导的肌肉质量增加的实质性贡献，然而，与径向生长不同， 肌纤维的纵向生长似乎不需要mTORC1的信号。换句话说，我们初步的 数据表明，肌纤维的径向和纵向生长受到不同的信号通路的调节。 具体地说，我们认为肌纤维的径向生长是由mTORC1依赖的机制驱动的，该机制 我们称之为“肌原纤维扩张周期”，而肌原纤维的纵向生长是由 一种不依赖于mTORC1的机制，涉及肌节在称为 蝶形虫。为了测试这些假设的有效性，我们将使用先进的成像技术，各种基因 干预，机械负荷诱导增长的两个互补模型，以及我们最新的最新技术 这项技术使我们能够可视化和量化(以≤10 nm分辨率)NSP聚集的位置。 总体而言，预计这一项目的成果不仅将填补我们对 机械刺激如何调节肌肉质量，但它们也将为未来的研究建立框架，这些研究 旨在更好地了解这一极其重要的进程。

Project Summary / Abstract Mechanical signals play a major role in the regulation of skeletal muscle mass, and the maintenance of muscle mass contributes significantly to disease prevention and quality of life. Although the link between mechanical signals and the regulation of muscle mass has been recognized for decades, the mechanisms that control this process remain ill-defined. For instance, most studies indicate that the mechanically induced growth of skeletal muscle is driven by an increase in the size of the existing myofibers rather than an increase in the number of myofibers. Moreover, current models assert that the increase in myofiber size is mediated by an increase in the balance between the rates of protein synthesis and protein degradation which, in turn, leads to the accumulation of newly synthesized proteins (NSPs) and the concomitant structural changes that drive the growth response. For instance, it is well known that an increase in mechanical loading can lead to microstructural changes such as the radial growth of myofibers. Surprisingly, however, the ultrastructural adaptations that drive these microstructural changes have not been defined. Indeed, a number of foundationally important questions such as whether the radial growth of myofibers is driven by an increase in the size and/or the number of myofibrils have not been answered. Likewise, the location(s) in which NSPs accumulate during mechanically induced growth (i.e., the sites of growth) are not known. As such, one of the major goals of this project is to fill these gaps in knowledge. Another major goal is to develop a better understanding of the signaling events that control the different aspects of mechanically induced growth. For instance, our previous work has established that signaling through mTORC1 plays a central role in the process via which mechanical stimuli induce the radial growth of myofibers. However, our preliminary data indicate that the longitudinal growth of myofibers can also make a substantive contribution to the mechanically induced accretion of muscle mass, yet, unlike radial growth, the longitudinal growth of myofibers does not appear to require signaling by mTORC1. In other words, our preliminary data suggest that the radial and longitudinal growth of myofibers are regulated by distinct signaling pathways. Specifically, we propose that the radial growth of myofibers is driven by a mTORC1-dependent mechanism that we have coined as the “myofibril expansion cycle”, whereas the longitudinal growth of myofibers is mediated by a mTORC1-independent mechanism that involves transverse Z-line splitting of sarcomeres at regions called sphenodes. To test the validity of these hypotheses we will use advanced imaging techniques, various genetic interventions, two complementary models of mechanical load-induced growth, and our new state-of-the-art technology that enables us to visualize and quantify (with ≤10 nm resolution) where NSPs accumulate. Collectively, it is anticipated that the outcomes of this project will not only fill major gaps in our understanding of how mechanical stimuli regulate muscle mass, but they will also build the framework for future studies that are aimed at developing a better understanding of this highly important process.