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

确定驱动骨骼肌机械诱导生长的结构适应

• 批准号: 10711412
• 负责人: TROY A HORNBERGER
• 金额: $ 16.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711412
• 关键词: Ablation; Aging; Attenuated; Bed rest; Cachexia; Chronic; Coin; Data; Dependence; Disease; Electron Microscopy; Elements; Equilibrium; Event; Foundations; Future; Goals; Growth; Hypertrophy; Imaging Techniques; Immobilization; Knockout Mice; Knowledge; Link; Location; Maintenance; Mechanics; Mediating; Modeling; Muscle; Muscle function; Muscular Dystrophies; Myofibrils; Myopathy; Nature; Outcome; Physiological; Play; Process; Protein Biosynthesis; Public Health; Quality of life; Radial; Regulation; Resolution; Role; Sarcomeres; Series; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Stimulus; Techniques; Technology; Testing; Visualization; Weight; Work; disorder prevention; gene therapy; improved; mechanical drive; mechanical load; mechanical signal; mechanical stimulus; mouse model; muscle form; protein degradation; resistance exercise; response; skeletal muscle growth; skeletal muscle wasting; therapy development

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.

项目摘要 /摘要 机械信号在调节骨骼肌质量和肌肉的维持中起主要作用 质量对预防疾病和生活质量产生了重大贡献。虽然机械之间的联系 信号和肌肉质量的调节已被认可数十年，这些机制控制了这一点 过程仍然不确定。例如，大多数研究表明机械诱导骨骼的生长 肌肉是由于现有肌纤维的大小增加而不是增加的肌肉 肌纤维。此外，当前模型断言，肌纤维大小的增加是通过增加的 蛋白质合成速率和蛋白质降解的速率之间的平衡，这又导致积累 新合成的蛋白质（NSP）和驱动生长反应的伴随结构变化。 例如，众所周知，机械负载的增加会导致微结构变化 作为肌纤维的径向生长。但是，令人惊讶的是，驱动这些的超微结构改编 微观结构变化尚未定义。确实，许多基本重要的问题，例如 肌纤维的径向生长是否由肌原纤维的大小和/或 没有回答。同样，NSP在机械诱导的生长过程中积累的位置 （即，生长地点）尚不清楚。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的信号事件 机械诱导的生长的不同方面。例如，我们以前的工作已经确定了信号 通过MTORC1通过机械刺激诱导径向生长的过程中的核心作用 肌纤维。但是，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积聚的实质性贡献，但与径向生长不同， 肌纤维的纵向生长似乎不需要MTORC1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。 具体而言，我们建议肌纤维的径向生长是由MTORC1依赖性机制驱动的 我们认为是“肌原纤维膨胀周期”，而肌纤维的纵向生长是由 MTORC1独立的机制，涉及在称为区域的肉瘤的横向z线分裂 脾脏。为了测试这些假设的有效性，我们将使用高级成像技术，各种遗传 干预措施，两种完整的机械负荷诱导的增长模型，以及我们的新最先进的 使我们能够可视化和量化NSP累积的技术。 总体而言，预计该项目的结果不仅会填补我们对 机械刺激如何调节肌肉质量，但它们还将建立以后研究的框架 旨在更好地了解这一非常重要的过程。