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

摘要 代谢功能障碍，临床表现为代谢综合征(MetSyn)，是一种重要的健康 由于肥胖症的高发病率以及与肥胖症和2型糖尿病的强烈关联，这在美国引发了一场危机。 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。我的 实验室对结构重建在调节线粒体中所起的作用非常感兴趣。 功能和细胞胰岛素的作用。线粒体重构是通过裂变-融合动力学实现的，并且 这些过程的损害与代谢性疾病和肌肉的病理生物学有关。 衰老过程中的消瘦。然而，线粒体重塑肌肉代谢之间的分子联系 和肌肉质量还没有得到充分的了解。我们之前已经展示了线粒体的裂变 DRp1信号受损介导的功能不全是代谢和胰岛素紊乱的基础 抵抗。在这里，我们展示了骨骼肌特异性敲除线粒体分裂调节因子 动力蛋白相关蛋白1(Drp1)复制了MetSyn的特征，包括葡萄糖耐量、脂肪 蓄积和胰岛素抵抗。我们提供了Drp1与琥珀酸酯共定位的证据。 脱氢酶复合体组装因子2(Sdhaf2)控制氧化代谢。此外，我们观察到 一种独特而戏剧性的肌肉萎缩表型伴随线粒体DNA(MtDNA)耗竭 可诱导的Drp1基因敲除小鼠模型。我假设Drp1对肌肉的维持是必不可少的 代谢功能和线粒体DNA稳定性部分通过其对琥珀酸脱氢酶/线粒体的作用 复合体II.这一假说将使用结构性和条件性肌肉特异性DRp1缺失来检验 小鼠：mDrp1HET和miDrp1KO。在目标1中，将使用细胞和动物研究来研究 Drp1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Drp1在SDH/Complex II活性调节中的作用。在目标3中，我们将确定 Drp1调节骨骼肌mtDNA拷贝数和肌重的机制。这些建议 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和线粒体动力学缺陷与 MetSyn与2型糖尿病相关肌病的特点

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.