Mitochondrial DNA Signatures of Poor Aerobic Exercise Trainability in Young Adults Born Preterm

Young adults born very preterm (VPTB; ≤ 32 weeks gestational age) have an impaired response to aerobic exercise training (AET), often characterized by no change in aerobic capacity (VO2max) following AET. This diminishes the potential of AET to offset their elevated cardiovascular disease risk early in life VPTB\'s poor trainability is linked to their known mitochondrial dysfunction, thought to occur due to blunted mitochondrial maturation with early birth. Currently, no therapeutics are available to improve VO2max trainability for this population. Data from our lab in humans and mice demonstrate that mitochondrial DNA (mtDNA) variants and other mitochondrial genomic aspects have a role in VO2max trainability. In humans, the investigators found that individuals with the largest increase in VO2max following AET had a higher occurrence of mitochondrial heteroplasmy (a shift in sequence across mtDNA). In contrast, heteroplasmy decreased in those with little-to-no change in VO2max. The reduction in heteroplasmy correlated with higher mtDNA lesions, suggesting exercise was inflicting excessive oxidative stress on mitochondria in these individuals. The investigators also identified 13 mtDNA variants in those with poor trainability, possibly linked to their lowered heteroplasmy response after exercise training. These data indicate that genetic diversity characterized by the response of mtDNA heteroplasmy with AET is an important factor determining the adaptability of VO2max with AET. To date, VPTB mitochondrial genomes have not been characterized. An onset of variants in their mitogenomes due to early birth would be easily identifiable compared to their birth mother, given that mtDNA is maternally inherited. Importantly, these mitogenome variants may inform the effect of AET on heteroplasmy and their low trainability. Thus, there is a critical need to characterize VPTB mitochondrial genome characteristics and how AET influences these dynamics. Our long-term goal is to improve mitochondrial function and VO2max trainability in VPTB young adults facing disproportionately higher disease risk where exercise is known to be beneficial as a treatment and preventative measure. Accordingly, the overall objectives of this application are to i) characterize VPTB-induced mtDNA changes in sequence, heteroplasmy, and damage, and ii) determine the effect of AET on these mtDNA traits and mitochondrial function in cells known to correlate with heart mitochondrial oxidative capacity: namely peripheral blood mononuclear cells (PBMCs). Our central hypothesis is that VTPB young adults will have unique mtDNA variants/mutations and that AET will significantly decrease PBMC mtDNA heteroplasmy and copies alongside lowered mitochondrial oxidative capacity compared to normal-term birth (NTB) adults. The rationale for this project is that characterizing unique VPTB mtDNA aspects and the heteroplasmy response to AET might reveal an underlying mechanism for their poor trainability that can be targeted for future work. To meet these objectives, the investigators will assess these two specific aims: Aim 1: Assess for informative mtDNA variants in VPTB young adults. The investigators hypothesize there will be de novo mtDNA variants in VPTB offspring compared to their birth mothers. Aim 2: Determine the effect of AET on mitochondrial oxidative capacity and mtDNA heteroplasmy, copy number, and lesions in isolated PBMCs in VPTB and NTB young adults. The investigators hypothesize VPTB adults will exhibit decreased mtDNA heteroplasmy and increased lesions following AET compared to age-matched NTB adults. After completing the proposed research, our expected outcome is identifying a unique signature of mtDNA variants and heteroplasmy responses to AET in VPTB adults that will explain their low trainability. These results are expected to have a positive impact for researchers because it will provide a foundation for future research to target mtDNA as a strategy to help VPTB adults reduce their risk for cardiovascular disease and improve their quality of life.