Alcohol-induced muscle damage in C. elegans

酒精引起的秀丽隐杆线虫肌肉损伤

• 批准号: 9035741
• 负责人: Hongkyun Kim
• 金额: $ 22.43万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-10 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035741
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Apoptotic; Atrophic; Autophagocytosis; Bioenergetics; Biogenesis; Caenorhabditis elegans; Cardiomyopathies; Cell Death; Cell Size; Cellular Stress Response; Chronic; Complex; Data; Defect; Equilibrium; Ethanol; Ethanol toxicity; Event; Exhibits; FRAP1 gene; Genetic study; Health; Heavy Drinking; Impairment; Intervention; Knowledge; Lead; Mammals; Mediating; Microfilaments; Mitochondria; Mitochondrial Proteins; Molecular; Movement; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Mutation; Myopathy; Nematoda; Oxygen Consumption; Pathway interactions; Phenotype; Post-Translational Protein Processing; Production; Proteins; Rhabdomyolysis; Role; Severities; Signal Pathway; Signal Transduction; Skeletal Muscle; Stress; Striated Muscles; Symptoms; Testing; Time; Tissues; Toxic effect; Tubular formation; alcohol abuser; alcohol exposure; alcoholic myopathy; base; binge drinking; biological adaptation to stress; cellular targeting; economic cost; mutant; problem drinker; protein misfolding; public health relevance; reduced muscle mass; research study; response; socioeconomics; therapeutic target

 DESCRIPTION (provided by applicant): Alcohol abuse is a major health issue with enormous socio-economic costs. Muscle is one of the major tissues that are negatively impacted by alcohol abuse. While binge drinking causes acute muscle damage such as rhabdomyolysis (muscle fiber dissolution), chronic alcohol abusers suffer from alcoholic muscle disease, such as cardiomyopathy or myopathy. Previous studies in the mammalian muscle showed that habitual alcohol consumption impairs mitochondria function. Along with the unique role of mitochondria in apoptotic cell death, the alcohol-induced impairment in mitochondrial function may explain partially muscle weakness and the atrophy-like symptoms in chronic alcoholic muscle disease. Recent studies have demonstrated that alcohol influences mitochondrial fusion and fission dynamics, which in turn modulates mitochondrial bioenergetics, autophagy and other signaling pathways. However, it is also recognized that chronic alcohol intake causes an array of adverse changes in cellular events and signaling pathways, including reduced mTOR (mechanistic target of rapamycin) signaling and cellular stress responses. One important question that has arisen from these studies is how these altered events and pathways are related to the dynamics of mitochondrial fusion and fission in the context of alcohol toxicity. Are these events and pathways sequential or causal to altered mitochondrial dynamics? Do the cellular events and pathways influence mitochondrial dynamics or vice versa if they occur independently of each other? Understanding their relationship will provide the basis for the identification of effective therapeutic targets. The nematode C. elegans is an excellent model organism that has widely been used to dissect complex cellular events and pathways, such as stress response and apoptotic cell death. We found that the C. elegans muscle exhibited changes in mitochondrial tubular networks upon ethanol exposure. In addition, we observed that chronic alcohol exposure reduced muscle size compared to controls, implicating the involvement of the mTOR signaling pathway that controls cell size and mitochondria biogenesis. Finally, chronic alcohol exposure to C. elegans resulted in the mitochondrial unfolded protein response (UPRmt). The induction of UPRmt by chronic alcohol exposure indicates that alcohol causes mitochondrial protein misfolding. Together, our data showed that alcohol preferentially targets mitochondrial function in muscle. In this exploratory proposal, we will define the inter-relationship between alcohol-induced mitochondrial dynamics and other cellular events or pathways. First, we will define the molecular components responsible for alcohol-mediated muscle mitochondrial fission. Second, we will determine the relationship between UPRmt and mTOR signaling and the alcohol-induced change in mitochondrial dynamics. The successful completion of this project will lead to a better understanding of how alcohol-induced mitochondrial fission interacts with other signaling pathways implicated in alcoholic muscle diseases. Hence, our study will reveal effective therapeutic targets for ameliorating alcohol-induced muscle disease.

 描述（由申请人提供）：酒精滥用是一个重大的健康问题，具有巨大的社会经济成本。肌肉是受酒精滥用负面影响的主要组织之一。虽然酗酒会导致急性肌肉损伤，如横纹肌溶解（肌纤维溶解），慢性酒精滥用者会患上酒精性肌肉疾病，如心肌病或肌病。先前对哺乳动物肌肉的研究表明，习惯性饮酒会损害线粒体功能。沿着线粒体在凋亡细胞死亡中的独特作用，酒精诱导的线粒体功能损伤可以部分解释慢性酒精性肌肉疾病中的肌无力和萎缩样症状。最近的研究表明，酒精影响线粒体融合和分裂动力学，进而调节线粒体生物能量学，自噬和其他信号通路。然而，人们也认识到，长期酒精摄入会导致细胞事件和信号传导途径的一系列不利变化，包括mTOR（雷帕霉素的机制靶点）信号传导和细胞应激反应减少。从这些研究中出现的一个重要问题是，这些改变的事件和途径如何与酒精毒性背景下线粒体融合和裂变的动力学相关。这些事件和途径是否与线粒体动力学的改变有关？细胞事件和途径是否会影响线粒体动力学，或者如果它们彼此独立发生，则反之亦然？了解它们之间的关系将为确定有效的治疗靶点提供基础。线虫C.线虫是一种极好的模式生物，其已被广泛用于剖析复杂的细胞事件和途径，例如应激反应和凋亡性细胞死亡。我们发现C.在乙醇暴露后，线虫肌肉表现出线粒体管状网络的变化。此外，我们观察到，与对照组相比，长期酒精暴露会减少肌肉大小，这意味着控制细胞大小和线粒体生物发生的mTOR信号通路的参与。最后，慢性酒精暴露于C。elegans引起线粒体未折叠蛋白反应（UPRmt）。慢性酒精暴露诱导UPRmt表明酒精导致线粒体蛋白质错误折叠。总之，我们的数据表明，酒精优先靶向肌肉中的线粒体功能。在这个探索性的建议中，我们将定义酒精诱导的线粒体动力学和其他细胞事件或途径之间的相互关系。首先，我们将定义负责酒精介导的肌肉线粒体分裂的分子组成部分。其次，我们将确定UPRmt和mTOR信号传导与酒精诱导的线粒体动力学变化之间的关系。该项目的成功完成将有助于更好地了解酒精诱导的线粒体裂变如何与酒精性肌肉疾病中涉及的其他信号通路相互作用。因此，我们的研究将揭示改善酒精诱导的肌肉疾病的有效治疗靶点。