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: 10705262
• 负责人: Paul Martin Coen
• 金额: $ 45.54万
• 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/10705262
• 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; DNA; Data; East Asian; Elderly; Etiology; European; Freezing; Genetic; Genetic Epistasis; Genome; Genomics; Goals; Haplogroup; Haplotypes; Healthcare; High Prevalence; Human; Incidence; Individual; Inherited; Knee Osteoarthritis; 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; Sampling; Single Nucleotide Polymorphism; Site; Skeletal Muscle; Thinness; Time; Training Programs; Variant; Walking; Woman; age related; aged; 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.

项目概要 老年人失去行动能力并导致残疾，这在老年人群中是一个严重的医疗保健问题 美国人口老龄化。此外，老年非裔美国人行动障碍的发生率更高 与白人相比。这些观察结果背后的机制尚不清楚。 我们已经证明线粒体功能是骨骼肌支持步行速度的关键特性， 老年人的身体机能和心肺健康。横断面和纵向研究表明 线粒体含量和功能水平较低，心肺健康较差，行走速度减慢 随着衰老。我们最近证明非裔美国人骨骼肌中线粒体功能较低 与白人女性相比，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尚未得到证实。 探索过。我们新颖的初步数据表明 mtDNA 单倍型是较低的重要决定因素 非裔美国人的线粒体功能和心血管健康。我们还表明线粒体DNA 变异与老年 AA 和 C 成年人的步行速度有关。此外，最近的研究表明 研究表明，运动训练计划导致的峰值摄氧量变化与 mtDNA 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、心血管功能的纵向下降 老年人的健康状况和步行速度。线粒体 DNA 的变异已被证明会影响衰老 表型可分为1）遗传变异，是母系遗传的单核苷酸 多态性 (SNP)，其中许多可以区分 mtDNA 单倍群，而许多则不能，或 2) 获得性变异，包括异质性，或任意位点突变 mtDNA 与正常 mtDNA 的百分比 随着年龄的增长，基因组和线粒体DNA拷贝数减少。 这项《肌肉、活动能力和衰老研究》的辅助研究将探讨遗传和后天的作用 大量表型良好的肌肉活检中线粒体功能的 mtDNA 变化 人类。我们还将探讨核编码线粒体蛋白 (NEMP) 和串扰的作用 观察线粒体DNA和核DNA之间的线粒体和生理差异。我们 将这些发现与整个队列中临床上重要的活动终点以及在 非裔美国人的流动性下降幅度更大。 我们的研究将首次表明线粒体 DNA 变异可预测线粒体和 生理功能，与行动障碍有关。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有功能低下风险的人并实施有针对性的治疗 疗法，例如体力活动，已被证明可以改善线粒体功能。