Mitochondrial genetics in skeletal muscle aging

描述(申请人提供)：骨质疏松症，与年龄相关的肌肉质量和力量的丧失，是导致虚弱和其他衰老下降的重要因素。许多病因都有牵连，越来越多的证据表明线粒体和线粒体基因组可能起着核心作用。最近的研究表明，氧化损伤与线粒体突变、线粒体功能障碍、纤维萎缩和丢失等一系列事件有关。目前提案中的研究通过对线粒体突变率的遗传操作来检验早期工作中观察到的相关性。我们的初步数据表明，过氧化氢酶和核酸外切酶缺陷的聚合酶γ突变小鼠的线粒体靶向性分别是线粒体突变率降低和增加的重要模型。这些模型将测试衰老过程中线粒体突变的因果关系，并精确定位适合干预的区域。我的目标是成为一名研究衰老基本机制的独立研究员，并开发出造福于我的老年患者的疾病修正疗法。在拟议的资助期内，我将在小鼠遗传学、饲养和群体管理、卫星细胞分离和培养以及用流式细胞仪测量线粒体功能方面获得新的技能。这些技术充分利用了华盛顿大学现有的资源，包括内森·霍克衰老生物学卓越中心和转基因资源实验室，以及我的导师和合作者的国际公认的专业知识。具体目标1：检验以下假设：全身性氧化损伤的减少将减少与年龄相关的线粒体遗传和酶异常，并改善骨质疏松症。具体目标2：检验线粒体DNA突变全身性增加将增加与年龄相关的线粒体遗传和酶异常并加重骨质疏松症的假设。具体目的3：利用条件线粒体突变小鼠，检测骨骼肌对mtDNA突变表型选择性表达的敏感性，并建立mtDNA缺失突变的发生与生物影响之间的关系。 相关性：拟议的研究将揭示骨骼肌随年龄增长而发生的基本变化，这些变化是导致脆弱的主要因素。阐明肌肉老化的基本机制将为防止这种与年龄相关的下降提供治疗干预要点。此外，这一职业发展奖将支持一位在老年学和老年医学领域工作的内科科学家的独特职业生涯，这两个领域的公共卫生需求日益增长。

DESCRIPTION (provided by applicant): Sarcopenia, the age-related loss of muscle mass and strength, is a significant contributor to frailty and other declines of aging. Many etiologies have been implicated and there is growing evidence that mitochondria and the mitochondrial genome may play a central role. Recent studies suggest a series of events linking oxidative damage to mitochondrial mutations, mitochondrial dysfunction, fiber atrophy and loss. The studies in the current proposal test the correlations observed in earlier work through the genetic manipulation of mitochondrial mutation rate. Our preliminary data show that the mitochondrial targeting of catalase and exonuclease-deficient polymerase gamma mutant mice are important models of decreased and increased mitochondrial mutation rate, respectively. These models will test the causality of mitochondrial mutations in the aging process and pinpoint areas amenable to intervention. My goal is to become an independent investigator studying basic mechanisms of aging and develop disease-modifying therapies that will benefit my older patients. During the proposed funding period, I will acquire new skills in the areas of mouse genetics, husbandry and colony management, satellite cell isolation and culture, and the measurement of mitochondrial function by flow cytometry. These techniques take full advantage of the resources available at the University of Washington, including the Nathan Shock Center of Excellence in the Biology of Aging and the Transgenic Resource Laboratory, in addition to the internationally-recognized expertise of my mentors and collaborators. Specific Aim 1: Test the hypothesis that systemic decreases in oxidative damage will decrease age-associated mitochondrial genetic and enzymatic abnormalities and ameliorate sarcopenia. Specific Aim 2: Test the hypothesis that systemic increases in mtDNA mutations will increase age- associated mitochondrial genetic and enzymatic abnormalities and worsen sarcopenia. Specific Aim 3: Using a conditional mitochondrial mutator mouse, I will test the susceptibility of skeletal muscle to selective expression of the mtDNA mutator phenotype and establish the relationship between occurrence and biological impact of mtDNA deletion mutations. RELEVANCE: The proposed studies will uncover the basic changes that occur with aging in skeletal muscle which are major contributors to frailty. Elucidating the basic mechanisms of muscle aging will suggest points for therapeutic intervention to prevent this age-related decline. Additionally, this Career Development Award will support the unique career of a physician-scientist working in the areas of gerontology and geriatric medicine, for which there is a growing public health need.