Mechanism by which fatty acid metabolism impacts muscle maintenance

脂肪酸代谢影响肌肉维持的机制

• 批准号: 10656381
• 负责人: MIN HAN
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656381
• 关键词: Animals; Attention; Behavior; Biochemical; Biological Process; Caenorhabditis elegans; Cell physiology; Coenzyme A Ligases; Cues; Data; Defect; Degenerative Disorder; Development; Disease; Embryo; Embryonic Development; Event; Fasting; Fatty Acids; Fatty acid glycerol esters; Food deprivation (experimental); Gene Expression; Genetic; Gluconeogenesis; Glucosylceramides; Goals; Guanosine Triphosphate Phosphohydrolases; Human; Intestines; LIMS1 gene; Link; Lipolysis; Maintenance; Mediating; Membrane; Metabolism; Molecular; Movement; Muscle; Muscle Cells; Muscle function; Muscular Atrophy; Myopathy; Neurons; Oogenesis; Outcome Study; Pathogenesis; Pathologic; Pathway interactions; Physiological; Play; Postembryonic; Process; Production; Proteins; Publications; Regulation; Repression; Research; Role; Sarcomeres; Series; Signal Transduction; Starvation; Striated Muscles; Structure; Testing; Tissues; Work; age related; apical membrane; branched chain fatty acid; endoplasmic reticulum stress; experimental study; fatty acid metabolism; genetic approach; genetic regulatory protein; insight; membrane polarity; myristoylation; nervous system disorder; reproductive; reproductive development; response; sarcopenia; sensor; sex determination; young adult

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.

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 膜形成），脂肪酸（FAS）的可用性深刻影响起始和 动物中各种细胞和发育事件的进展。特别是，脂肪或FA水平具有 长期以来一直提出促进生殖发育，以及神经元和肌肉功能 在禁食条件下觅食能力。广泛的研究还揭示了原因/效应关系 FA代谢异常和病理状况之间，包括与年龄有关的神经系统和 肌肉疾病。但是，FA水平对特定生理的影响的基础机制 功能，尤其是特定组织中FA敏感机制调节的功能，已经是 尚未得到充实的。我们最近的研究发现，酰基-COA合成酶和蛋白肉豆蔻酰化作用为一种 种系中的FA传感器通过调节性别确定来调节卵子发生的发作。 基于这一发现，我们建议阐明FA可用性调节肌肉的机制 维护并提供有关FA代谢相关退行性的发病机理的见解 疾病。我们已经获得了大量的初步数据，用于假设肉豆蔻酰化不足 在两个ARF GTPase和肌肉中的其他蛋白质中，介导FA缺乏对肌膜的影响 通过诱导与已知参与的ER应力和展开的蛋白质反应（UPR）（UPR）的完整性 主要疾病的起源。我们提出了三项具体研究旨在进一步调查的研究 假设和基本机制。在AIM 1中，我们将同时使用分子和遗传方法 确定肉豆蔻酰化在肌肉中的作用，以维持肌节的完整性。 Myristoylation水平和 将检查特定调节因素的亚细胞定位，以介导介导的作用 FA水平的肌肉功能变化。在AIM 2中，我们将分析ER应力和UPR的作用 介导肉豆蔻酰化缺乏对肌肉维护的影响。我们将首先描述ER 压力和3个UPR途径的变化在响应FA和肉豆蔻酰化缺乏方面。我们将 然后测试实验诱导ER应力是否导致肌肉缺陷，与肉豆蔻酰化相似 缺乏症以及抑制ER压力是否可以挽救肉豆蔻酰化下的肌肉功能 不足。对于AIM 3，我们将注意力转向理解如何肉豆蔻的压力 影响肌肉完整性。我们将使用两种系统的方法，一种表达式分析引发的， 一个基于抑制器屏幕的一个，以搜索与在 FA/肉豆蔻酰化缺乏引起的肌肉缺陷。我们已经开始分析一个有希望的 候选人UNC-97/Pinch似乎在此过程中起着重要作用。拟议的研究 将在我们对FA代谢对肌肉功能的影响的理解方面取得重大进步。