Mitochondrial haplotype and sex modulate responses to endurance exercise training

Heterogeneity in the response to exercise training is widely demonstrated in the literature. Although the variability in exercise acclimation is not entirely understood, a large portion of exercise response variability is attributable to genetic heritability potentially due to inherited maternal mitochondrial characteristics. Humans exhibit a heterogenous genome and mitochondrial haplotype; however much of the preclinical research proposed to investigate molecular transducers of exercise has been implemented using mouse models that lack mitochondrial and nuclear genomic diversity. Leveraging a novel rat model of heterogeneous genome, OKC-HET rats, we investigated the impact of mitochondrial (mt) haplotype on exercise training. We hypothesized that rats with divergent mitochondrial genomes will respond differently to endurance exercise training. OKC-HET rats aged 18-19 months old were subjected to 8 weeks of voluntary wheel running as their endurance exercise training programme. We found mt haplotype-specific effects on responses to endurance exercise and motor co-ordination, which were consistent with mitochondrial bioenergetics and markers of oxidative stress. Mitochondrial copy number and the expression of mitochondrial proteins were similar between the two mt haplotypes, suggesting intrinsic alterations of mitochondrial functions by the two distinct mitochondrial genomes. Motor co-ordination and fragmentation of acetylcholine receptors were also affected by mitochondrial haplotype. The mt haplotype effects on training responses were specific to biological sex also. Collectively we report that mitochondrial haplotype significantly affects responses to endurance exercise in a sex-specific manner. KEY POINTS: Mitochondrial haplotype affects the responses to endurance exercise. Sex modulates the effects of mitochondrial haplotype in the responses to endurance training. Mitochondrial DNA (mtDNA) deletion frequency increases following endurance exercise. mtDNA deletion frequency is higher in males than females after endurance exercise in OKC-HET rats.