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 老年人经历了导致残疾的流动性丧失，这是一个严重的医疗保健问题 美国人口老龄化。此外，在非裔美国人中，流动性残疾的发病率更大 与高加索人相比。这些观察结果背后的机制尚不清楚。 我们已经表明，线粒体功能是支持步行速度的骨骼肌的关键特性， 老年人的身体功能和心肺健康。横截面和纵向研究表明 线粒体含量和功能的较低水平，较低的心肺健康和步行速度降低 随着衰老。我们最近在非裔美国人的骨骼肌中表现出较低的线粒体功能 与较低的心血管适应性和代谢率有关的高加索女性相比。 线粒体DNA（mtDNA）在年龄相关的肌肉氧化能力变化中的作用尚未 探索。我们的新型初步数据表明，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。我们还显示了mtDNA 变体与年龄较大的AA和C成年人的步行速度有关。此外，最近的研究已经 揭示了VO2的峰值变化响应于运动训练计划与mtDNA有关 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。已证明会影响衰老的mtDNA的变化 表型可以分为1）遗传的遗传变体，它们是母体遗传的单核苷酸 多态性（SNP），其中许多分化了mtDNA单倍群，许多不区分，或2） 获得的变异，包括异质，或在任何位点的突变麦克DNA的百分比 基因组和降低的mtDNA拷贝数，随着衰老而发生。 这项对肌肉，流动性和衰老研究的辅助研究将探讨继承和获得的作用 肌肉活检中线粒体功能中mtDNA的变化 人类。我们还将探讨核编码线粒体蛋白（NEMP）和串扰的作用 线粒体DNA和核DNA之间观察到的线粒体和生理差异之间。我们 将把这些发现与整个队列中临床上重要的移动性终点相关联，以及 非裔美国人流动性的流动性较高。 我们的研究将是第一个表明mtDNA变异可以预测线粒体和 生理功能，与迁移障碍有关。这些发现可以使我们能够评估 使用简单的血液抽血来识别有低功能的风险并实施目标的mtDNA变异 疗法，例如体育锻炼，已证明可以改善线粒体功能。