Mechanisms of Protection in the Brain by Physical Exercise in Polg Mutator Mice

描述（由申请人提供）：体育锻炼与帕金森病（PD）的风险呈负相关，并且在啮齿类动物中可以防止MPTP诱导的线粒体功能障碍和神经元丢失。最近，运动也被证明对表达线粒体DNA （mtDNA）聚合酶（Polg）校对缺陷形式的Polg“突变”小鼠具有显着的保护作用。在这些小鼠中，存在体细胞mtDNA突变的加速积累，导致过早衰老表型。运动使这些小鼠的肌肉线粒体功能正常化，并显著延长寿命。也许更令人惊讶的是，体育锻炼还能改善大脑线粒体功能，完全防止脑萎缩。大脑中这些保护作用的机制尚不清楚。在骨骼肌中，运动可增加PGC-1 mRNA水平，PGC-1是一种转录辅助激活因子，可上调线粒体生物发生和抗氧化防御。运动也可能通过翻译后机制增加PGC-1的活性。在肌肉中，运动可以降低RIP140的水平，RIP140是PGC-1活性的抑制因子，并诱导SIRT1依赖性的PGC-1去乙酰化，从而促进其激活。我们假设运动对脑线粒体功能的保护作用可能是由类似的机制产生的，这种机制可以解释肌肉的这种作用。如果正确，那么这些机制可以解释运动与降低PD风险之间的联系。鉴于最近的数据表明大脑PGC-1活性降低与帕金森病的发病机制有关，锻炼和PGC-1活性增加之间的潜在联系尤其令人兴奋。因此，增加大脑中PGC-1¿是一种很有前途的潜在神经保护策略。Polg突变小鼠为研究运动对大脑的保护作用提供了一个有价值的模型。除了脑萎缩和受损

DESCRIPTION (provided by applicant): Physical exercise is inversely related to the risk of Parkinson's disease (PD), and in rodents can protect against mitochondrial dysfunction and neuronal loss induced by MPTP. Recently, exercise also has been shown to have a dramatic protective effect in Polg "mutator" mice expressing a proofreading deficient form of the mitochondrial DNA (mtDNA) polymerase ¿ (Polg). In these mice, there is an accelerated accumulation of somatic mtDNA mutations, leading to a premature aging phenotype. Exercise in these mice normalizes muscle mitochondrial function and significantly extends lifespan. Perhaps more surprisingly, physical exercise also improves brain mitochondrial function and completely prevents brain atrophy. The mechanisms of these protective effects in the brain are unknown. In skeletal muscle, exercise increases levels of mRNA of PGC-1¿, a transcriptional coactivator that upregulates mitochondrial biogenesis and antioxidant defenses. Exercise also may increase PGC-1¿ activity through posttranslational mechanisms. In muscle, exercise reduces levels of RIP140, a suppressor of PGC-1¿ activity, and induces SIRT1 dependent deacetylation of PGC-1¿, thereby promoting its activation. We hypothesize that the protective effects of exercise on brain mitochondrial function exercise may result from similar mechanisms that account for this effect in muscle. If correct, then these mechanisms may account for the association of exercise with a reduced risk of PD. This potential link between exercise and increased PGC-1¿ activity is particularly exciting in light of recent data implicating reduced brai PGC-1¿ activity in the pathogenesis of PD. Thus, increasing PGC-1¿ in brain is a promising potential neuroprotective strategy. The Polg mutator mice represent a valuable model for studying the protective effects of exercise on the brain. In addition to brain atrophy and impaired mitochondrial function, we have preliminary data indicating that the Polg mutator mice have significant behavioral (motor) deficits as well as loss of striatal tyrosine hydroxylase (TH) immunostaining intensity and reduced dopamine (DA) and dopamine metabolites, indicating that mitochondrial dysfunction caused by somatic mtDNA mutation accumulation can cause nigral-striatal pathology. These data raise the possibility that the high levels of somatic mtDNA mutations that we and others have identified in SN neurons in PD may contribute to nigral-striatal dysfunction in PD. Thus, if our hypothesis proves to be correct, then the proposed studies on the impact of exercise on somatic mtDNA mutations and PGC-1¿ activity in the brain may be of relevance to PD. The main goal of this project is to investigate potential mechanisms of the protective effect of physical exercise in the brain of Polg mutator mice, including the impact on somatic mtDNA mutation levels and on regulation of PGC-1¿ levels and activity in the brain. This targeted approach will be complemented by an unbiased metabolomics approach that may reveal a role for novel pathways linking exercise to protective effects in the brain. PUBLIC HEALTH RELEVANCE: Physical exercise improves mitochondrial function and has robust protective effects in the brain, but the mechanisms of these effects are unknown. Understanding these mechanisms provide insights into novel neuroprotective strategies of relevance to aging and age-related neurodegenerative diseases such as Parkinson's disease. We now propose to investigate the mechanisms of protection in the brain by exercise through studies of a mouse model of premature aging.