The effect of mitochondrial genome heterogeneity on voluntary wheel running activity in aged rats

Abstract

Introduction: Variation in the response to exercise training is a widely accepted concept. A large portion of exercise response variability is attributable to genetic heritability, potentially due to inherited maternal mitochondrial characteristics. Importantly, humans exhibit a heterogenous mitochondrial genome. Unfortunately, many preclinical models used to investigate molecular transducers of exercise training are inbred rodent models that lack mitochondrial diversity, which has poor translatability to humans. Recently, a rat model has been generated to reflect human mitochondrial genome heterogeneity. Hence, we propose using this rat model to investigate the impact of mitochondrial genome heterogeneity on voluntary wheel running (VWR) activity. Objective: To investigate the effect of mitochondrial genome heterogeneity on VWR activity in aged rats. Hypothesis: VWR activity will differ between two rat strains with divergent mitochondrial genomes. Methodology: Male and female OKC-HETB and OKC-HETW rats were obtained from the Oklahoma City VA Medical Center. Briefly, the OKC-HETB and OKC-HETW rat strains were generated by a four-way cross strategy using four inbred strains (Brown Norway [BN], Fischer 344, Lewis, and Wistar Kyto [WKY]). Subsequent reciprocal crosses between males and females from the two F1 hybrids were made to generate genetically heterogeneous rats with mitochondrial genomes from either the BN (OKC-HETB) or WKY (OKC-HETW) parental strains. As a result, OKC-HETB and OKC-HETW rats have equal numbers of alleles yet divergent mitochondrial genomes. Endurance capacity and neuromuscular function in 18-to 20-month-old rats were assessed by treadmill running and rotarod protocols before and after 8 weeks of VWR. After post-testing, animals are euthanized at 21-24 months old, and tissues are collected. The mitochondrial function of obtained tissues will be analyzed via high-resolution respirometry, and protein levels will be quantified using immunohistochemistry and Western blotting. Results: Current baseline data shows female rats weighed less than males, which was not affected by strain. Although no strain effect on treadmill performance was observed, females ran longer than males during the treadmill test. However, this sex effect was lost within strain comparisons. There was no strain effect on rotarod performance as latency to fall times were similar between strains. However, OKCHetW rats showed some improved latency to falls over time. Female OKC-HETB rats had a longer latency to falls at baseline than their male counterparts, which became similar between the sexes over time. Conversely, female OKC-HETW rats developed longer latency to falls compared to their male counterparts over time. Currently, 2 weeks of VWR activity was highly variable among rats in the W stain but similar among rats in the B strain. Conclusions: Our preliminary findings suggest that mitochondrial genome heterogeneity does not impact baseline physical function outcomes such as endurance capacity and neuromuscular function in exercise naïve 18-20 months old rats. However, biological sex appears to have a greater influence. Currently, strain and sex did not affect 2-weeks of VWR activity. However, this study is currently ongoing using an 8-week VWR intervention. Importantly, this study will evaluate the impact of mitochondrial genome heterogeneity on VWR adaptations in young and aged rats. Wake Forest University School of Medicine Start-up Funds to Ahn. R21 AG072137 to Richardson, Stout, and Austad. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.