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

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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.