Mitochondrial Function and mtDNA Deletions in Sarcopenia

描述（由申请人提供）：有证据表明，氧化应激增加和/或抗氧化防御下降导致的线粒体DNA （mtDNA）年龄相关缺失达到临界阈值，导致细胞损伤并最终导致肌肉质量和功能的丧失。我们建议通过31P磁共振波谱（31P MRS）来确定线粒体功能的非侵入性体内测量是否与线粒体功能和线粒体DNA缺失（mtDNA）的体外（活检）测量相关，并研究肌肉减少症和非肌肉减少症老年人的长期身体功能/身体活动、营养/补充剂摄入与这些测量之间的关系。我们假设，与年龄和性别匹配的非肌少症老年人相比，老年肌少症患者身体更虚弱，线粒体功能障碍和mtDNA缺失的证据也更多。该提案将利用一种新的、多学科的方法，使用体内肌肉线粒体功能测量（31P MRS）和体外线粒体功能活检测量（复合体I和IV活性和mtDNA缺失）来更好地定义肌肉减少症、线粒体功能和mtDNA缺失之间的关系。28名健康的非肌少症和老年肌少症受试者将进行动态31P MRS测试（线粒体功能）和同一块肌肉的骨骼肌活检，以确定线粒体功能（复合体I和IV活性）和mtDNA缺失。将对现有的关于身体活动、身体功能、营养和维生素/补充剂摄入的5 - 10年的纵向数据以及这些措施的相关关系进行调查。由于骨骼肌减少症与老年人残疾的增加有关，将这些发现转化为具有临床结果的新干预措施的对照试验，将使我们能够开始揭示不同疗法可能导致更好地识别处于危险中的老年人的精确机制，并改进预防或逆转骨骼肌减少症的方法。

DESCRIPTION (provided by applicant): There is evidence that age-related deletions in mitochondrial DNA (mtDNA) secondary to increased oxidative stress and/or decreased antioxidant defense reach a critical threshold, resulting in cellular damage and ultimately the loss of muscle mass and function. We propose to determine if the non-invasive in vivo measure of mitochondrial function by 31Phosphorus magnetic resonance spectroscopy (31P MRS), is correlated to in vitro (biopsy) measures of mitochondrial function and mitochondrial DNA deletions (mtDNA), and to investigate the relationships between long-term physical function/physical activity, and nutritional/supplement intake with these measures in sarcopenic and non-sarcopenic elderly. We hypothesize that older sarcopenic adults will be more frail physically and display significantly more evidence of mitochondrial dysfunction and mtDNA deletions compared to age-and sex-matched non- sarcopenic elderly. This proposal will utilize a novel, multi-disciplinary approach using an in vivo measure of muscle mitochondrial function (31P MRS), and in vitro biopsy measures of mitochondrial function (Complex I and IV activities and mtDNA deletions to better define relationships between sarcopenia, mitochondrial function, and mtDNA deletions. Twenty-eight healthy non-sarcopenic, and sarcopenic elderly subjects will have a dynamic 31P MRS test (mitochondrial function) and a skeletal muscle biopsy in the same muscle to determine mitochondrial function (Complex I and IV activities) and mtDNA deletions. Five -ten years of existing longitudinal data on physical activity, physical function, nutrition, and vitamin/supplement intake and these measures will be investigated for associated relationships. As sarcopenia is related to increasing disability in the elderly, the translation of these findings to controlled trials of novel interventions with clinical outcomes, will allow us to begin to uncover the precise mechanisms by which different therapies may lead to better identification of aging adults at risk, and improved approaches for the prevention or reversal of sarcopenia.