Mechanism by which fatty acid metabolism impacts muscle maintenance

项目摘要 由于它们在基本生物过程中的重要作用（例如，能源生产和 膜形成），脂肪酸（FAs）的可用性深刻地影响了启动和 动物中各种细胞和发育事件的进展。特别是，脂肪或FA水平 长期以来一直被认为是促进生殖发育，以及神经和肌肉功能， 禁食条件下的觅食能力。广泛的研究也揭示了因果关系 FA代谢异常与病理状况之间的关系，包括与年龄相关的神经系统和 肌肉疾病。然而，FA水平对特定生理功能影响的潜在机制 功能，特别是在特定组织中由FA敏感机制调节的功能， 探索不足我们最近的研究发现，酰基辅酶A合成酶和蛋白质肉豆蔻酰化作为一种 生殖细胞中的FA传感器通过调节性别决定来调节卵子发生的开始。 基于这一发现，我们建议阐明FA可用性调节肌肉的机制 维持和提供深入了解FA代谢相关的退行性变的发病机制， 疾病我们已经获得了广泛的初步数据，假设肉豆蔻酰化缺乏 两种ARF GTP酶和肌肉中的其他蛋白质介导FA缺乏对肌节的影响， 通过诱导ER应激和未折叠蛋白反应（UPR）来实现完整性，已知这些反应参与 重大疾病的起源。我们提出了三个具体的研究目标，以进一步探讨这一点 假设和潜在机制。在目标1中，我们将使用分子和遗传方法 以确定肉豆蔻酰化在肌肉中维持肌节完整性的作用。豆蔻酰化水平和 将检查特定调节因子的亚细胞定位在介导以下效应中的作用： FA水平变化对肌肉功能的影响。在目标2中，我们将分析ER应激和UPR在 介导豆蔻酰化缺乏对肌肉维持的影响。我们将首先描述ER 应激和3种UPR途径对FA和豆蔻酰化缺陷的反应变化。我们将 然后测试实验诱导ER应激是否会导致与肉豆蔻酰化类似的肌肉缺陷 缺乏，以及抑制ER应激是否可以拯救肉豆蔻酰化下的肌肉功能 缺陷对于目标3，我们将把我们的注意力转向理解肉豆蔻酰化和ER应激是如何 影响肌肉完整性。我们将使用两个系统的方法，一个表达分析启动， 一种是基于抑制筛选，以寻找作用于UPRER下游或与UPRER平行的因素， FA/豆蔻酰化缺陷诱导的肌肉缺陷。我们已经开始分析一个有希望的 候选人，1997/PINCH，似乎在这个过程中发挥了重要作用。拟议研究 将使我们对脂肪酸代谢对肌肉功能的影响的理解取得重大进展。

Project Summary Due to their essential roles in fundamental biological processes (e.g., energy production and membrane formation), the availability of fatty acids (FAs) profoundly impacts the initiation and progression of various cellular and developmental events in animals. In particular, fat or FA levels have long been proposed to promote reproductive development, as well as neuronal and muscle functions for foraging ability under fasting conditions. Extensive studies have also revealed a cause/effect relationship between abnormal FA metabolism and pathologic conditions, including age-related neurological and muscular diseases. However, mechanisms underlying the impact of FA levels on specific physiological functions, especially functions regulated by FA-sensing mechanisms in specific tissues, have been underexplored. Our recent study found that an acyl-coA synthetase and protein myristoylation act as a FA sensor in the germline to regulate the onset of oogenesis by modulating the sex-determination. Based on this finding, we propose to elucidate the mechanisms by which FA availability regulates muscle maintenance and provide insights into the pathogenesis of FA metabolism-related degenerative diseases. We have obtained extensive preliminary data for a hypothesis where myristoylation deficiency of two ARF GTPases, and other proteins in muscle, mediate the impact of FA deficiency on sarcomere integrity by inducing ER stress and unfolded protein responses (UPR) that are known to be involved in the genesis of major diseases. We proposed three specific research aims to further investigate this hypothesis and the underlying mechanism. In Aim 1, we will use both molecular and genetic approaches to determine the role of myristoylation in muscle to maintain sarcomere integrity. Myristoylation level and subcellular localization of specific regulatory factors will be examined for roles in mediating the effect of FA level change on muscle functions. In Aim 2, we will analyze the role of ER stress and UPR in mediating the impact of myristoylation deficiency on muscle maintenance. We will first characterize ER stress and changes in the 3 UPR pathways in responding to FA and myristoylation deficiency. We will then test if experimentally inducing ER stress causes muscle defects similar to that from myristoylation deficiency, and whether repressing ER stress can rescue the muscle functions under myristoylation deficiency. For Aim 3, we will turn our attention to understanding how myristoylation and ER stress impact muscle integrity. We will use two systematic approaches, one expression analysis-initiated and one based on a suppressor screen, to search for factors that act downstream of or in parallel to UPRER in FA/myristoylation deficiency-induced muscle defects. We have already started analyzing one promising candidate, UNC-97/PINCH, that appears to play a significant role in the process. The proposed research will make significant advances in our understanding of the impact of FA metabolism on muscle functions.