Impact of mitochondrial genetics on muscle oxidative capacity, fitness, and mobility in older adults

线粒体遗传学对老年人肌肉氧化能力、健康和活动能力的影响

• 批准号: 10522044
• 负责人: Paul Martin Coen
• 金额: $ 47.08万
• 依托单位: ADVENTHEALTH ORLANDO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522044
• 关键词: Address; Admixture; Adult; African; African American; African American population; Aging; Alzheimer' s Disease; Amerindian; Ancillary Study; Basal metabolic rate; Biological; Biopsy; Biopsy Specimen; Blood; Blood Cells; Caucasians; Clinical; Complex; Cross-Sectional Studies; DNA; DNA copy number; Data; East Asian; Elderly; Etiology; European; Freezing; Genetic; Genetic Epistasis; Genome; Genomics; Goals; Haplogroup; Haplotypes; Healthcare; High Prevalence; Human; Incidence; Individual; Inherited; Knee Osteoarthritis; Lead; Link; Longevity; Longitudinal Studies; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Muscle; Muscle Mitochondria; Muscle function; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Phenotype; Physical Fitness; Physical Function; Physical activity; Physiological; Play; Population; Property; Race; Respiration; Risk; Role; Single Nucleotide Polymorphism; Site; Skeletal Muscle; Thinness; Time; Training Programs; Variant; Walking; Woman; age related; aged; base; cardiorespiratory fitness; cardiovascular fitness; cohort; design; disability; disability risk; exercise training; experience; fitness; genome wide association study; heteroplasmy; human disease; improved; men; metabolic rate; novel; personalized approach; phenotypic data; precision medicine; prevent; racial determinant; racial difference; response; targeted treatment; walking speed

PROJECT SUMMARY Older adults experience a loss of mobility that leads to disability, which is a serious health care issue in an aging US population. Furthermore, the incidence of mobility disability is greater in older African Americans compared to Caucasians. The mechanisms behind these observations are not well understood. We have shown that mitochondrial function is a key property of skeletal muscle that supports walking speed, physical function, and cardiorespiratory fitness in older adults. Cross-sectional and longitudinal studies reveal lower levels of mitochondrial content and function, lower cardiorespiratory fitness and slowing walking speed with aging. We recently demonstrated lower mitochondrial function in skeletal muscle in African American compared to Caucasian women that is associated with lower cardiovascular fitness and metabolic rate. The role of mitochondrial DNA (mtDNA) in age related changes in muscle oxidative capacity has not been explored. Our novel preliminary data suggest that mtDNA haplotype is an important determinant of lower mitochondrial function and cardiovascular fitness in African Americans. We have also shown that mtDNA variants are associated with walking speed in older AA and C adults. Furthermore, recent studies have revealed that change in peak VO2 in response to an exercise training program is associated with mtDNA haplogroup. Based on these observations we hypothesize that mtDNA haplotype plays an important role in cross sectional variation and more importantly, longitudinal declines in mitochondrial function, cardiovascular fitness, and walking speed in older adults. Variations in mtDNA that have been shown to impact aging phenotypes can be divided into 1) inherited variants, which are maternally inherited single nucleotide polymorphisms (SNPs), many of which differentiate the mtDNA haplogroups, and many that do not, or 2) acquired variation including heteroplasmy, or percentage of mutated vs normal mtDNA at any site across genome and decreased mtDNA copy number that occurs with aging. This ancillary study to The Study of Muscle, Mobility, and Aging will explore the role of inherited and acquired variations in mtDNA in mitochondrial function from muscle biopsies in a large cohort of well phenotyped humans. We will also explore the role of nuclear encoded mitochondrial proteins (NEMP) and crosstalk between mitochondrial DNA and Nuclear DNA in the mitochondrial and physiological differences observed. We will relate these findings to the clinically important endpoint of mobility in the entire cohort, as well as the role in the greater mobility declines in mobility in African Americans. Our study will be the first to show that mtDNA variation is predictive of greater declines in mitochondrial and physiological function, which are associated with mobility disability. These findings could allow us to assess mtDNA variation using a simple blood draw to identify those at risk for low function and to implement targeted therapies, e.g., physical activity, which has been shown to improve mitochondrial function.

项目摘要 老年人失去行动能力，导致残疾，这是一个严重的卫生保健问题， 美国人口老龄化。此外，老年非裔美国人的行动不便发生率更高 与高加索人相比。这些观察结果背后的机制还没有得到很好的理解。 我们已经证明，线粒体功能是骨骼肌的一个关键特性，支持步行速度， 老年人的身体功能和心肺功能。横向和纵向研究表明， 线粒体含量和功能水平较低，心肺功能较低，行走速度减慢 随着年龄的增长。我们最近证实了非裔美国人骨骼肌线粒体功能较低， 与高加索女性相比，这与较低的心血管健康和代谢率有关。 线粒体DNA（mtDNA）在与年龄相关的肌肉氧化能力变化中的作用还没有得到证实。 探讨了我们的新的初步数据表明，mtDNA单倍型是一个重要的决定因素， 非裔美国人的线粒体功能和心血管健康我们还发现mtDNA 变异与老年AA和C型成人的步行速度有关。此外，最近的研究表明， 研究表明，运动训练计划引起的峰值VO2变化与线粒体DNA相关， 单倍群基于这些观察，我们假设mtDNA单倍型在 横截面变化，更重要的是，线粒体功能的纵向下降，心血管 健身和老年人的步行速度。已被证明影响衰老的mtDNA变异 表型可分为1）遗传变异，其是母系遗传的单核苷酸 多态性（SNPs），其中许多可区分mtDNA单倍型组，而许多不能区分，或2） 获得性变异，包括异质性，或在任何位点突变与正常mtDNA的百分比， 随着年龄的增长，线粒体DNA拷贝数减少。 这项对肌肉、运动性和衰老研究的辅助研究将探讨遗传和获得性的作用。 在一个大的队列中，来自肌肉活检的线粒体功能中mtDNA的变异 人类我们还将探讨核编码线粒体蛋白（NEMP）和串扰的作用， 线粒体DNA和核DNA之间在线粒体和生理上的差异观察。我们 将这些发现与整个队列中的临床重要终点活动性以及 非裔美国人的流动性下降幅度更大。 我们的研究将是第一个表明mtDNA变异是线粒体和 生理功能，这与行动不便。这些发现可以让我们评估 mtDNA变异使用简单的抽血来识别那些处于低功能风险中的人，并实施有针对性的 治疗，例如，身体活动，这已被证明可以改善线粒体功能。