Role of dynamin-related protein 1 in the regulation of metabolism and skeletal muscle mass

动力相关蛋白1在代谢和骨骼肌质量调节中的作用

• 批准号: 10573326
• 负责人: Zhenqi Zhou
• 金额: $ 51.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573326
• 关键词: Adult; Aging; Animals; Architecture; Binding; Cardiovascular Diseases; Cell Respiration; Cells; Citric Acid Cycle; Clinical; Complex; Confocal Microscopy; Data; Dominant-Negative Mutation; Dynamin; Electron Transport; Energy Metabolism; Enzymes; Fatty acid glycerol esters; Functional disorder; Gene Expression; Glucose Intolerance; Health; Heterozygote; Impairment; In Vitro; Incidence; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Laboratories; Link; Lipids; Longevity; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial DNA; Molecular; Molecular Chaperones; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscular Atrophy; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Outcome; Oxidative Phosphorylation; Phenotype; Play; Process; Proteins; Public Health; Recombinant Proteins; Regulation; Research; Research Proposals; Rodent Model; Role; Secondary to; Signal Transduction; Skeletal Muscle; Spirometry; Succinate Dehydrogenase; Tamoxifen; Testing; Time; Tissues; combat; exercise training; fatty acid metabolism; fatty acid oxidation; gain of function; genetic regulatory protein; glucose disposal; in vivo; insulin sensitivity; interest; knock-down; mitochondrial dysfunction; mitochondrial genome; mortality; mouse model; muscle form; muscle metabolism; new therapeutic target; novel; oxidation

ABSTRACT Metabolic dysfunction, manifested clinically as the metabolic syndrome (MetSyn), is a significant health crisis in the US due to its high incidence and strong associations with obesity and type 2 diabetes. Mitochondrial dysfunction is a robust molecular underpinning contributing to key aspects of the MetSyn. My laboratory is keenly interested in the role that architecture remodeling plays in regulating mitochondrial function and cellular insulin action. Mitochondrial remodeling is achieved by fission-fusion dynamics, and impairment of these processes have been implicated in the pathobiology of metabolic disease and muscle wasting during aging. However, the molecular links between mitochondrial remodeling muscle metabolism and muscle mass are inadequately understood. We have previously shown the mitochondrial fission incompetence mediated by impaired Drp1 signaling underlies derangements in metabolism and insulin resistance. Herein we show that skeletal muscle-specific knockout of the mitochondrial fission regulator Dynamin-Related Protein 1 (Drp1) reproduces features of the MetSyn, including glucose intolerance, fat accumulation, and insulin resistance. We provide evidence that Drp1 colocalizes with succinate dehydrogenase complex assembly factor 2 (Sdhaf2) to control oxidative metabolism. Moreover, we observed a unique and dramatic muscle wasting phenotype along with mitochondrial DNA (mtDNA) depletion in the inducible Drp1 knockout mouse model. I hypothesize that Drp1 is essential for the maintenance of muscle metabolic function and mtDNA stability in part by its actions on succinate dehydrogenase (SDH)/mitochondrial complex II. This hypothesis will be tested using both constitutive and conditional muscle-specific Drp1 deletion mice: mDrp1HET and miDrp1KO. In Aim 1, both cellular and animal studies will be employed to investigate the effects of Drp1 deletion on mitochondrial function, muscle metabolism, and insulin sensitivity. In Aim 2, we will determine the role of Drp1 in the regulation of SDH/complex II activity. In Aim 3, we will determine the mechanisms of Drp1 in regulating skeletal muscle mtDNA copy number and muscle mass. These proposed studies are of important translational relevance as the research will elucidate the molecular mechanisms underlying mitochondrial dysfunction in skeletal muscle and link defective mitochondrial dynamics with features of MetSyn and type 2 diabetes mellitus-associated myopathy.

摘要 代谢功能障碍（Metabolic dysfunction，MS）是一种严重危害人类健康的疾病，临床表现为代谢综合征（Metabolic syndrome，MetSyn 由于其高发病率和与肥胖和2型糖尿病的密切联系，美国的糖尿病危机。 线粒体功能障碍是一个强大的分子基础，有助于MetSyn的关键方面。我 一个实验室对结构重塑在调节线粒体中的作用非常感兴趣 功能和细胞胰岛素作用。线粒体重塑是通过裂变-融合动力学实现的， 这些过程的损伤与代谢疾病和肌肉疾病的病理生物学有关 衰老过程中的损耗然而，线粒体重塑肌肉代谢之间的分子联系 和肌肉质量的认识不足。我们之前已经展示了线粒体分裂 由受损的Drp 1信号传导介导的功能不全是代谢和胰岛素紊乱的基础 阻力在此，我们发现骨骼肌特异性敲除线粒体裂变调节因子， 动力蛋白相关蛋白1（Drp 1）复制MetSyn的特征，包括葡萄糖耐受不良、脂肪 积累和胰岛素抵抗。我们提供的证据表明，Drp 1与琥珀酸共定位 脱氢酶复合物组装因子2（Sdf 2）来控制氧化代谢。此外，我们观察到， 一个独特的和戏剧性的肌肉萎缩表型沿着线粒体DNA（mtDNA）的消耗， 诱导型Drp 1敲除小鼠模型。我假设Drp 1对维持肌肉的生长至关重要。 代谢功能和线粒体DNA稳定性部分通过其对琥珀酸脱氢酶（SDH）/线粒体 复合体II。将使用组成性和条件性肌肉特异性Drp 1缺失来检验这一假设 小鼠：mDrp 1HET和miDrp 1 KO。在目标1中，将采用细胞和动物研究来研究 Drp 1缺失对线粒体功能、肌肉代谢和胰岛素敏感性的影响。在目标2中，我们将 确定Drp 1在调节SDH/复合物II活性中的作用。在目标3中，我们将确定 Drp 1调控骨骼肌mtDNA拷贝数和肌肉质量的机制。这些拟议 研究具有重要的翻译相关性，因为研究将阐明分子机制 骨骼肌中潜在的线粒体功能障碍，并将缺陷的线粒体动力学与 MetSyn和2型糖尿病相关肌病的特征。