Mitochondrial mutations as determinants of beneficial versus maleficial exercise response in mouse models for mitochondrial diseases (Mitosport)

线粒体疾病小鼠模型中线粒体突变是有益与有害运动反应的决定因素（Mitosport）

• 批准号: 418891524
• 负责人: Dr. Patrick Schaefer
• 金额: --
• 依托单位: Center for Mitochondrial and Epigenomic Medicine (CMEM)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418891524?language=en
• 关键词: Mitochondrial; mutations; determinants; beneficial; versus

Primary mitochondrial disorders are now recognized as the most common class of metabolic disorders affecting an estimate 1 in 4200 individuals. Furthermore, mitochondrial dysfunction has been implicated in a wide range of common diseases from diabetes to Alzheimer’s disease. Yet, there are no proven therapeutic interventions for mitochondrial disease. Exercise has been found to be beneficial for diabetes and Alzheimer’s disease indicating that appropriate exercise regimes might be beneficial for primary mitochondrial disease as well. However, primary mitochondrial diseases are genetically diverse involving hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Accordingly, I hypothesize that specific exercise regimes will be beneficial for some mitochondrial disorders but contraindicated in others dependent on the underlying mitochondrial defect.The Center for Mitochondrial and Epigenomic Medicine (CMEM) has developed a unique series of viable mouse models of mitochondrial disease, among which are mutations in the mtDNA complex I (ND6P25L) and IV (COIV421A) genes and in the adenine nucleotide translocator 1 (Ant1). These mutant mice encompass a wide range of mitochondrial dysfunction and thus provide an exceptional and powerful opportunity to expose different mitochondrial defects to controlled exercise regimes followed by detailed physiological and biochemical analyses. On the molecular level, exercise adaptions are mediated via metabolite and redox changes like the NAD/NADH ratio, which can be determined microscopically with high spatial resolution.By combining CMEM’s mouse models with my expertise in redox imaging I am now in a unique position to clarify the interrelation between mitochondrial mutations, exercise response, and the underlying molecular pathways. This will open the possibility of personalized clinical advice for mitochondrial patients regarding beneficial physical activity, as well as obtain deep insight into the therapeutic basis of exercise for common diseases.I will pursue 3 specific aims:Specific Aim 1: Determination of the exercise physiology of the mitochondrial mutant mice and their acute response to an exercise stimulus. The daily activity and the response to an acute exercise stress test (VO2max) will be assessed and correlated with changes in redox state, metabolite levels, signaling pathway changes and inflammatory response.Specific Aim 2: Assess the exercise adaptions of the mitochondrial mutant mice upon an exercise protocol. The mice will be exposed to a 6 week exercise protocol to assess their mitochondrial responses in physiology, respiratory complex activity, metabolites, and signaling pathways.Specific Aim 3: Elucidate the physiological basis of the exercise response by evaluating nicotinamide riboside and AICAR as exercise mimetics. I will evaluate the effects on exercise capacity of the mutant mice by altering their NAD/NADH ratio or ADP/ATP ratio specifically.

原发性线粒体疾病现在被认为是最常见的一类代谢疾病，估计每4200人中就有1人受到影响。 此外，线粒体功能障碍与从糖尿病到阿尔茨海默病的广泛的常见疾病有关。 然而，对于线粒体疾病没有经过证实的治疗干预。已经发现运动对糖尿病和阿尔茨海默病有益，这表明适当的运动方案也可能对原发性线粒体疾病有益。然而，原发性线粒体疾病是遗传多样性的，涉及线粒体DNA（mtDNA）和核DNA（nDNA）基因中的数百个突变。因此，我假设特定的运动方案对某些线粒体疾病有益，但对其他依赖于潜在线粒体缺陷的线粒体疾病是禁忌的。线粒体和表观基因组医学中心（CMEM）已经开发了一系列独特的线粒体疾病可行小鼠模型，其中包括mtDNA复合物I（ND 6P 25 L）和IV（COIV 421 A）基因以及腺嘌呤核苷酸转运子1（Ant 1）的突变。 这些突变小鼠包括广泛的线粒体功能障碍，因此提供了一个特殊的和强大的机会，暴露不同的线粒体缺陷，以控制运动方案，然后详细的生理和生化分析。在分子水平上，运动适应是通过代谢物和氧化还原变化介导的，如NAD/NADH比值，这可以在显微镜下以高空间分辨率测定。通过将CMEM的小鼠模型与我在氧化还原成像方面的专业知识相结合，我现在处于一个独特的位置，可以澄清线粒体突变，运动反应和潜在分子途径之间的相互关系。这将为线粒体病患者提供个性化的有益身体活动的临床建议，并深入了解运动对常见疾病的治疗基础。我将追求3个具体目标：具体目标1：确定线粒体突变小鼠的运动生理学及其对运动刺激的急性反应。评估每日活动和对急性运动应激试验（VO 2 max）的反应，并将其与氧化还原状态、代谢物水平、信号通路变化和炎症反应的变化相关联。具体目标2：评估运动方案后线粒体突变小鼠的运动适应性。 将小鼠暴露于6周的运动方案，以评估它们在生理学、呼吸复合物活性、代谢物和信号转导pathways.Specific Aim 3：通过评估烟酰胺核苷和AICAR作为运动模拟物来阐明运动反应的生理基础。 我将通过改变突变小鼠的NAD/NADH比值或ADP/ATP比值来评估突变小鼠对运动能力的影响。