Determination of circulation factors that mediate the health benefits of exercise in mitochondrial aging

项目摘要/摘要： 这项建议旨在检验耐力运动刺激循环因子释放的假设。 改善线粒体的适合性。CyteGen的目标是识别这些内生因素并对其进行改造 治疗以线粒体功能障碍为中心的疾病。这些疾病包括神经退行性疾病 以及其他与衰老有关的疾病，以及罕见的先天线粒体疾病 线粒体蛋白编码基因的错误会影响5000个人中的1个。目前，没有有效的 治疗方法是可用的。为了确定改善线粒体健康的因素，CyteGen使用了一种独特的 鼠标模型，由PI创建。这个模型显示了一种严重的线粒体综合症，寿命缩短。 唯一线粒体DNA Polg的核酸外切酶校对活性受损所致的跨度和早衰 聚合酶。Polg在小鼠和人类之间高度保守，该聚合酶有200多个突变 与人类疾病有关，这支持了CyteGen的观点，即老鼠的发现将 转化成人类。Polg突变小鼠耐力运动逆转早发性衰老综合征 通过克服线粒体功能的Polg缺陷。对运动小鼠组织的分析表明 内源性循环因素可能起了作用。我们将检验一个假设，即循环因素 运动产生的分泌物通过收集运动后的POLG血浆改善线粒体功能 小鼠和久坐不动的对照组，并将其注射到表现出线粒体功能降低的老年Polg小鼠中 骨骼肌和心脏功能受损。按照模拟运动的注射时间表 训练后，我们将检查代谢能力、心脏功能、自发活动水平和线粒体 功能。这项研究的第二个目标是使用基于细胞的模型来确定来自 运动对Polg突变细胞线粒体功能的影响。我们研究的目标是确定循环 逆转线粒体功能障碍的因素，具有适当的特性以支持临床前研究的启动 为临床评估做准备。

Project Summary/Abstract: This proposal seeks to test the hypothesis that endurance exercise stimulates the release of circulating factors that improve mitochondrial fitness. CyteGen’s goal is to identify these endogenous factors and engineer them to treat diseases in which mitochondrial dysfunction is central. These diseases include neurodegenerative and other diseases associated with aging, as well as the rare mitochondrial diseases that arise from inborn errors in genes encoding mitochondrial proteins that affect 1 in 5000 individuals. Currently, no effective treatments are available. To identify factors that improve mitochondrial fitness, CyteGen is using a unique mouse model, created by the PI. This model displays a profound mitochondrial syndrome with reduced life span and premature aging due to impaired exonuclease proofreading activity of POLG, the sole mtDNA polymerase. POLG is highly conserved between mice and humans and over 200 mutations in this polymerase have been associated with human disease, supporting CyteGen’s contention that mouse discoveries will translate into humans. Endurance exercise of POLG mutant mice reverses the early-onset aging syndrome by overcoming the POLG defect in mitochondrial function. Analyses of tissues in exercised mice suggests that endogenous circulating factors may be responsible. We will test the hypothesis that circulating factors secreted as a result of exercise improve mitochondrial function by collecting plasma from exercised POLG mice and sedentary controls and injecting it into old POLG mice that display reduced mitochondrial function and impaired skeletal muscle and cardiac function. Following a schedule of injections that mimics exercise training, we will examine metabolic capacity, cardiac function, spontaneous activity levels and mitochondrial function. A second aim of this study is to use cell based models to determine the effects of plasma from exercised mice on mitochondrial function of POLG mutant cells. The goal of our studies is to identify circulating factors that reverse mitochondrial dysfunction with suitable properties to support initiation of preclinical studies in preparation for clinical evaluation.