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.

项目概要 由于它们在基本生物过程（例如能源生产和 膜的形成），脂肪酸（FA）的可用性深刻影响启动和 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可以促进生殖发育以及神经元和肌肉功能 禁食条件下的觅食能力。广泛的研究还揭示了因果关系 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 水平对特定生理影响的潜在机制 功能，特别是特定组织中 FA 传感机制调节的功能，已被 尚未充分探索。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用 种系中的 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 FA 可用性调节肌肉的机制 维持并提供对 FA 代谢相关退行性病变发病机制的见解 疾病。我们已经获得了广泛的初步数据来证明肉豆蔻酰化缺陷的假设 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 重大疾病的发生。我们提出了三个具体的研究目标来进一步研究这一问题 假设和潜在机制。在目标 1 中，我们将使用分子和遗传学方法 确定肉豆蔻酰化在肌肉中维持肌节完整性的作用。肉豆蔻酰化水平和 将检查特定调节因子的亚细胞定位在介导的作用中的作用 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 调节肉豆蔻酰化缺陷对肌肉维持的影响。我们首先来描述 ER 应对 FA 和肉豆蔻酰化缺陷的 3 个 UPR 途径的压力和变化。我们将 然后测试通过实验诱导内质网应激是否会导致与肉豆蔻酰化类似的肌肉缺陷 缺乏，以及抑制内质网应激是否可以挽救肉豆蔻酰化下的肌肉功能 不足。对于目标 3，我们将把注意力转向了解肉豆蔻酰化和 ER 应激如何 影响肌肉完整性。我们将使用两种系统方法，一种是表达分析启动的方法，一种是基于表达分析的方法。 一种基于抑制子筛选的方法，寻找在 UPRER 下游或与 UPRER 并行作用的因子 FA/肉豆蔻酰化缺陷引起的肌肉缺陷。我们已经开始分析一项有前途的 候选者 UNC-97/PINCH 似乎在此过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。