Effects of insulin-like signaling, aging, and ubiquinone on C. elegans muscle

类胰岛素信号传导、衰老和泛醌对秀丽隐杆线虫肌肉的影响

基本信息

批准号：
8687954
负责人：
ALFRED L FISHER
金额：
$ 27.83万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8687954
关键词：
Adverse effects Aging Animals Area Caenorhabditis elegans Cellular biology Cholesterol Clinical Complex Development Drug usage Effectiveness Elderly Electron Microscopy Electron Transport Enzymes Functional disorder Generations Genes Genetic Histology Homologous Gene Hormones Human Hydroxymethylglutaryl-CoA reductase Impairment Insulin Insulin-Like Growth Factor I Intervention Lead Link Longevity Mammals Measures Metabolic Pathway Mevalonate kinase Mitochondria Mitochondrial Diseases Mitochondrial Electron Transport Complex II Motor Neurons Muscle Muscle Cells Muscle Weakness Muscle function Mutation Myalgia Myopathy Nematoda Nursing Homes Osteoporosis Output Oxidants Oxidative Stress Pathway interactions Pharmaceutical Preparations Physical Function Pravastatin Preclinical Drug Evaluation Process Production Protein-Energy Malnutrition Proteins Quality of life RNA Interference Relative (related person)Reporter Research Risk Factors Role Self Care Serum Signal Transduction Structure Testing Tissues Toxic effect Ubiquinone Vertebrates Work age effect age related bisphosphonate falls farnesyl pyrophosphate improved in vivo insight isoprenoid mevalonate mitochondrial dysfunction mortality muscle aging muscle form muscle strength muscular structure mutant novel prevent receptor response sarcopenia tool

项目摘要

DESCRIPTION (provided by applicant): Sarcopenia is the loss of muscle mass and muscle strength that occurs in aging people. The resulting loss of muscle strength contributes to impairments in physical functioning in older people and serves as a risk factor for loss of independence, need for nursing home placement, and ultimately mortality. Currently there are no treatments for sarcopenia and the cause(s) are incompletely understood. Hence there is a need to identify new ways to study sarcopenia and identify mechanisms that may be amenable to intervention. During aging, C. elegans develops sarcopenia, and mutations in the insulin/IGF-1 receptor daf-2 delay the development of sarcopenia. We have found that mvk-1, which is the worm homolog of the mevalonate kinase gene, is required for this delay. Mevalonate kinase is involved in the conversion of mevalonate to isoprenoids, ubiquinone, and cholesterol, and this enzyme lies in a metabolic pathway targeted by the commonly used statin medications. Statins have well-known toxic effects on muscle, but the cause of these adverse effects is still under active study. Among ubiquinone, isoprenoids, and cholesterol, we have found ubiquinone to be the required output of the mevalonate pathway with regards to muscle aging. Ubiquinone is the electron acceptor for complex I and complex II of the mitochondrial electron transport chain. Prior work has shown that daf-2 mutants have elevated complex I and II activity, and mitochondrial activity is better preserved in the daf-2 mutants during aging compared to wild-type animals. Additionally, complex I activity in muscle and other tissues declines during aging in vertebrates. These findings led us to hypothesize that mitochondrial activity is a driver of the development of sarcopenia during aging and perhaps is involved in statin toxicity. To test this hypothesis we propose to (1) examine muscle structure during aging in wild-type worms, daf-2 mutants, and daf-2 mutants with reduced ubiquinone levels; (2) test whether aging and low ubiquinone levels impair mitochondrial ATP production or (3) lead to increased ROS production during aging; (4) determine the consequences of directly manipulating complex I activity both up and down on muscle function; and (5) conduct a pilot compound screen using drugs used for genetic mitochondrial illnesses to test for improvements in muscle function during aging. A novel aspect of our work will be the use of recently developed fluorescent proteins to longitudinally and non-invasively measure cellular ATP levels and ROS production in the muscles of aging animals. Together our project can provide insights into the roles of mitochondrial dysfunction in muscle during aging or in response to impaired ubiquinone synthesis due to medications such as statins.

描述（由申请人提供）：肌少症是指老年人发生的肌肉质量和肌肉力量的丧失。由此导致的肌肉力量丧失会导致老年人身体机能受损，并成为丧失独立性、需要入住疗养院以及最终死亡的危险因素。目前尚无针对肌肉减少症的治疗方法，其原因尚不完全清楚。因此，需要找到研究肌肉减少症的新方法并确定可能适合干预的机制。在衰老过程中，线虫会出现肌肉减少症，而胰岛素/IGF-1 受体 daf-2 的突变会延迟肌肉减少症的发生。我们发现，mvk-1（甲羟戊酸激酶基因的蠕虫同源物）是这种延迟所必需的。甲羟戊酸激酶参与甲羟戊酸向类异戊二烯、泛醌和胆固醇的转化，并且该酶位于常用他汀类药物的代谢途径中。他汀类药物对肌肉具有众所周知的毒性作用，但这些不良作用的原因仍在积极研究中。在泛醌、类异戊二烯和胆固醇中，我们发现泛醌是甲羟戊酸途径与肌肉衰老相关的所需输出。泛醌是线粒体电子传递链复合物 I 和复合物 II 的电子受体。先前的研究表明，daf-2 突变体具有较高的复合物 I 和 II 活性，并且与野生型动物相比，daf-2 突变体在衰老过程中线粒体活性得到更好的保存。此外，在脊椎动物的衰老过程中，肌肉和其他组织中的复合物 I 活性会下降。这些发现使我们推测线粒体活动是衰老过程中肌肉减少症的发生可能与他汀类药物的毒性有关。为了检验这一假设，我们建议 (1) 检查野生型线虫、daf-2 突变体和泛醌水平降低的 daf-2 突变体在衰老过程中的肌肉结构； (2) 测试衰老和低泛醌水平是否会损害线粒体 ATP 生成或 (3) 导致衰老过程中 ROS 生成增加； (4) 确定直接上下调节复合物 I 活性对肌肉功能的影响； (5) 使用用于遗传性线粒体疾病的药物进行试点化合物筛选，以测试衰老过程中肌肉功能的改善情况。我们工作的一个新颖方面是使用最近开发的荧光蛋白来纵向和非侵入性地测量衰老动物肌肉中的细胞 ATP 水平和 ROS 产生。我们的项目可以共同深入了解线粒体功能障碍在衰老过程中或对因他汀类药物等药物导致的泛醌合成受损的反应中的作用。