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基本作用(例如，能源生产和 膜的形成)，脂肪酸(FAs)的有效性深刻地影响着 动物体内各种细胞和发育事件的进展。特别是，脂肪或FA水平有 长期以来，人们一直建议促进生殖发育，以及促进神经和肌肉功能 在禁食条件下的觅食能力。广泛的研究也揭示了因果关系。 FA代谢异常与病理情况之间的关系，包括与年龄相关的神经和 肌肉疾病。然而，FA水平对特定生理指标的影响机制 功能，特别是在特定组织中由FA传感机制调节的功能，已经被 开发不足。我们最近的研究发现，酰辅酶A合成酶和蛋白质肉豆蔻酰化作用是一种 胚系中的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，我们建议阐明脂肪酸可用性调节肌肉的机制 维护并为FA代谢相关退行性变的发病机制提供见解 疾病。我们已经获得了大量的初步数据，以支持肉豆蔻酰化缺陷的假说 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 通过诱导内质网应激和已知参与的未折叠蛋白反应(UPR)来实现完整性 重大疾病的起源。我们提出了三个具体的研究目标来进一步研究这一问题。 假说和潜在的机制。在目标1中，我们将同时使用分子和遗传方法 确定肉豆蔻酸化在肌肉中维持肌节完整性的作用。肉豆蔻化水平和 将考察特定调控因子的亚细胞定位在调节 FA水平变化对肌肉功能的影响。在目标2中，我们将分析内质网应激和UPR在 介导肉豆蔻酰化缺陷对肌肉维持的影响。我们将首先描述ER的特征 3条UPR通路对FA和肉豆蔻酰化缺陷的应激和变化。我们会 然后测试实验诱导的内质网应激是否会导致与肉豆蔻酸化类似的肌肉缺陷 缺乏，抑制内质网应激是否能挽救肉豆蔻化作用下的肌肉功能 缺乏症。对于目标3，我们将把注意力转向了解肉豆蔻化和内质网应激 影响肌肉的完整性。我们将使用两种系统方法，一种是由表达式分析发起的，另一种是 一种基于抑制者筛选，以搜索在UPRER下游或与UPRER并行的因素 FA/肉豆蔻酰化缺陷引起的肌肉缺陷。我们已经开始分析一个很有希望的 候选人UNC-97/PINCH似乎在这一进程中发挥了重要作用。拟议的研究 将在我们理解FA代谢对肌肉功能的影响方面取得重大进展。

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.