Association Between Mitochondrial Dna Sequence, Heteroplasmy, And Indels With Response To Aerobic Exercise Training

PURPOSE: Aerobic exercise training provides numerous biological and physiological health benefits towards the prevention and treatment of various chronic diseases. However, not all individuals increase cardiorespiratory fitness (CRF) with exposure to a given dose of aerobic training: some individuals are highly trainable and increase CRF, while others respond poorly. Genetic background is known to contribute to interindividual variation in adaptations to aerobic training. Our current understanding of genetics and exercise is limited primarily to the nuclear genome as only a few laboratories have investigated the role of the mitochondrial genome. The purpose of this study was to determine whether mitochondrial DNA (mtDNA) sequence, heteroplasmy, and indels differed among individuals previously characterized as elite endurance athletes, and high- or low-responders to aerobic training. METHODS: DNA was isolated from whole blood in healthy subjects part of the GENATHLETE (world class endurance athletes; n=15) and HERITAGE (CRF response levels: high responders n=15; low responders n =15) study cohorts. mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries and sequenced on a Miseq instrument. Unique mtDNA sequence variants were called when at least two individuals in a group had the variant. RESULTS: Compared to athletes and high-responders, low-responders had unique mtDNA single nucleotide polymorphisms (SNPs) in D-loop (displacement-loop) hypervariable region (HVR) 2 at positions 72, 152, 185, 188, 228, 295, 462, and 489. Of the HVR2 positions, position 188 was unique only to low-responders. Indels were unique to athletes and high-responders and located in D-loop HVR1 (16179, 16182, 16188, 16192), HVR2 (302), and HVR3 (567) positions. mtDNA Heteroplasmy was not different between groups. CONCLUSIONS: Our results highlight an area of the mitochondrial genome responsible for DNA replication and transcription that may contribute to an individual's ability to improve CRF with aerobic training. Ongoing work aims to 1) confirm present findings in low responders through increasing sample size from the HERITAGE cohort, and 2) test for interactions between mitochondrial and nuclear genomes associated with response to a given dose of aerobic training.