Adaptive Responses to Exercise Training Are Modulated by Mitochondrial Haplotype

Variation in the response to exercise training is a widely demonstrated topic by previous research. A large portion of exercise training response variability is attributable to genetic heritability, potentially due to the inherited maternal mitochondrial genome. Importantly, humans exhibit a heterogenous genome and mitochondrial haplotype, and yet much of the preclinical research investigating molecular transducers of exercise training have been implemented using inbred mouse models that lack mitochondrial and nuclear genomic diversity. A rat model has been recently generated to reflect heterogenous human mitochondrial genomes. Leveraging the unique rat model (i.e., OKC-HET rats), we investigated the impact of mitochondrial genome on exercise training responses. We hypothesized that rats with divergent mitochondrial genomes will respond differently to endurance exercise training. 19 months old OKC-HET rats were subjected to 8 weeks of voluntary wheel running as their endurance exercise training program. We found genotype-specific effects on adaptive responses to endurance exercise and motor coordination, which were consistent with mitochondrial bioenergetics and markers of oxidative stress. Mitochondrial copy number and the expression of mitochondrial electron transport proteins were similar between the genotypes, suggesting intrinsic alterations of mitochondrial functions by the two distinct mitochondrial genomes. Motor coordination and fragmentation of acetylcholine receptors were also affected by mitochondrial haplotype. Collectively, we report that mitochondrial haplotype has direct impacts on physical function measures such as endurance capacity and motor coordination in genetically heterogeneous rats after exercise training. Given the 94 nucleotide differences between the two mitochondrial haplotypes, future research should focus on identifying specific mitochondrial genes contributing to the genotype differences in endurance exercise training responses. BA was funded by NIA R00AG064143. AR was funded by NIA AG072137. JW was funded from the NIH R01AG055518, R01AG069924, K02AG059847 and from Veterans Affairs I01RX004521. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.