Mitochondrial genetics in skeletal muscle aging

描述（由申请人提供）：肌肉减少症，即与年龄相关的肌肉质量和力量损失，是导致虚弱和其他衰老下降的重要因素。许多病因学已被牵连，越来越多的证据表明，线粒体和线粒体基因组可能发挥核心作用。最近的研究表明，一系列事件将氧化损伤与线粒体突变、线粒体功能障碍、纤维萎缩和损失联系起来。当前提案中的研究通过线粒体突变率的遗传操作来测试早期工作中观察到的相关性。我们的初步数据表明，线粒体靶向过氧化氢酶和核酸外切酶缺陷的聚合酶γ突变小鼠的线粒体突变率降低和增加，分别是重要的模型。这些模型将测试线粒体突变在衰老过程中的因果关系，并确定适合干预的领域。我的目标是成为一名独立的研究人员，研究衰老的基本机制，并开发出有益于老年患者的疾病改善疗法。在拟议的资助期间，我将获得小鼠遗传学，饲养和群体管理，卫星细胞分离和培养，以及通过流式细胞术测量线粒体功能等领域的新技能。这些技术充分利用了华盛顿大学的资源，包括内森·休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：氧化损伤的全身性减少将减少与年龄相关的线粒体遗传和酶异常，并改善肌肉减少症。具体目标二：检验线粒体DNA突变的系统性增加将增加与年龄相关的线粒体遗传和酶异常并使肌肉减少症恶化的假设。具体目标3：使用条件性线粒体突变小鼠，我将测试骨骼肌的敏感性选择性表达的mtDNA突变表型，并建立mtDNA缺失突变的发生和生物学影响之间的关系。 相关性：拟议的研究将揭示骨骼肌老化的基本变化，这些变化是脆弱的主要原因。阐明肌肉衰老的基本机制将为预防这种与年龄相关的衰退的治疗干预提供建议。此外，该职业发展奖将支持在老年学和老年医学领域工作的医生科学家的独特职业生涯，这是一个日益增长的公共卫生需求。

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.