Mitochondrial Dysfunction in Aged Muscle

描述（由申请人提供）：线粒体在将细胞呼吸与细胞存活联系起来方面起关键作用，并且是许多年龄相关的退行性病理学中的关键要素：衰老的线粒体理论提出，氧化损伤导致不可逆的线粒体功能障碍和随年龄的组织退化.在上一个资助周期开发的新的非侵入性方法已经揭示了在老年小鼠和人类骨骼肌中体内测量的显著的线粒体解偶联，这至少是部分可逆的。该建议基于这些发现来评估：1）随着年龄的增长体内线粒体功能障碍的潜在机制，以及2）线粒体功能障碍的每个组分的可逆性。我们采用最先进的光学和磁共振光谱方法来量化体内线粒体ATP和O2通量随年龄的变化。这些缺陷的生化基础是从相同小鼠肌肉的体外组织分析中确定的。我们研究了一系列年龄段的野生型小鼠，以评估氧化损伤的积累如何与自然衰老中的线粒体缺陷和功能障碍相关。具有改变的抗氧化活性和解偶联蛋白（UCP 3）表达的转基因模型被用于鉴定这种功能障碍的潜在机制。目的1检测氧化损伤和解偶联蛋白活性在野生型和转基因小鼠线粒体偶联丧失（P/O降低）中的作用。目的2确定呼吸链缺陷如何损害体内呼吸功能。我们在野生型和转基因小鼠的多个年龄段对62通量的体内测量与对特定线粒体组分的氧化损伤的测量进行配对。目的3测试目的1和2中测量的线粒体缺陷和功能障碍的可逆性。耐力运动用于增加线粒体增殖和周转，从而替换受损的线粒体并改善功能。拟议的研究与人类健康的相关性是双重的。1)确定导致线粒体功能障碍的特定生化机制将确定潜在的策略，以延缓或逆转随着年龄的线粒体病理。2)我们的长期目标是开发非侵入性方法来诊断线粒体功能障碍，并跟踪旨在逆转老年人残疾的干预措施的进展。

DESCRIPTION (provided by applicant): Mitochondria play a key role in linking cell respiration to cell survival and are critical elements in many age- related degenerative pathologies: The mitochondrial theory of aging proposes that oxidative damage leads to irreversible mitochondrial dysfunction and tissue degeneration with age. New non-invasive methods developed in the last grant cycle have revealed significant mitochondrial uncoupling measured in vivo in aged mouse and human skeletal muscle that is at least partially reversible. This proposal builds on these findings to evaluate: 1) the mechanisms underlying in vivo mitochondrial dysfunction with age, and 2) the reversibility of each component of mitochondrial dysfunction. We employ state-of-the-art optical and magnetic resonance spectroscopic approaches to quantify in vivo deficits in mitochondrial ATP and Oz fluxes with age. The biochemical bases of these deficits are determined from in vitro tissue analysis of the same mouse muscles. We study wild-type mice over a range of ages to evaluate how accumulation of oxidative damage is related to mitochondrial defects and dysfunction in natural aging. Transgenic models with altered antioxidant activities and uncoupling protein (UCP3) expression are used to identify the underlying mechanisms of this dysfunction. Aim 1 tests the roles of oxidative damage and uncoupling protein activity in the loss of mitochondrial coupling (reduced P/O) with age in wild-type and transgenic mice. Aim 2 determines how respiratory chain defects impair respiratory function in vivo. We pair in vivo measurements of 62 flux with measures of oxidative damage to specific mitochondrial components at multiple ages in wild- type and transgenic mice. Aim 3 tests the reversibility of the mitochondrial defects and dysfunction measured in Aims 1 and 2. Endurance exercise is used to increase mitochondrial proliferation and turnover, thereby replacing damaged mitochondria and improving function. The relevance of the proposed research to human health is two-fold. 1) The determination of the specific biochemical mechanisms leading to mitochondrial dysfunction will identify potential strategies to retard or reverse mitochondrial pathologies with age. 2) Our long-term goal is the development of non- invasive methods to diagnose mitochondrial dysfunction and follow the progress of interventions meant to reverse disability in the elderly.