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

项目总结/摘要 机械信号在骨骼肌质量的调节和肌肉的维持中起着重要的作用 大众对预防疾病和提高生活质量作出了重大贡献。虽然机械之间的联系 信号和肌肉质量的调节已经被认识了几十年，控制这一点的机制 过程仍然不明确。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尺寸的增加而不是肌纤维数量的增加驱动的。 肌纤维此外，目前的模型断言，肌纤维大小的增加是由肌纤维的增加介导的。 蛋白质合成和蛋白质降解速率之间的平衡，这反过来又导致蛋白质的积累。 新合成的蛋白质（NSP）和随之而来的结构变化，驱动生长反应。 例如，众所周知，机械载荷的增加可导致微观结构变化， 如肌纤维的放射状生长。然而，令人惊讶的是，驱动这些细胞的超微结构适应性 微观结构的变化尚未确定。事实上，一些基本的重要问题，如 无论肌纤维的径向生长是由肌原纤维的尺寸和/或数量的增加驱动的， 没有得到答复。同样，在机械诱导生长期间NSP积累的位置 (i.e.,生长的部位）未知。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理解控制细胞凋亡的信号事件。 机械诱导生长的不同方面。例如，我们以前的工作已经确定， 通过mTORC 1在机械刺激诱导细胞径向生长的过程中起着核心作用。 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 实质性的贡献，机械引起的增长的肌肉质量，然而，不像径向增长， 肌纤维的纵向生长似乎不需要mTORC 1的信号传导。换句话说，我们的初步 数据表明肌纤维的径向和纵向生长受不同的信号通路调节。 具体来说，我们提出肌纤维的径向生长是由mTORC 1依赖性机制驱动的， 我们创造了“肌原纤维扩张周期”，而肌纤维的纵向生长是由 一种mTORC 1独立机制，涉及肌节在称为 蝶骨为了验证这些假设的有效性，我们将使用先进的成像技术， 干预措施，两个互补的模型机械负荷引起的增长，和我们的新的国家的最先进的 该技术使我们能够可视化和量化（分辨率≤10 nm）NSP的积累。 总的来说，预计该项目的成果不仅将填补我们在理解 机械刺激如何调节肌肉质量，但他们也将为未来的研究建立框架， 旨在更好地了解这一非常重要的过程。

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.