INFLUENCE OF GENETIC BACKGROUND ON HEART MITOCHONDRIAL DNA LESIONS AND COPY NUMBER IN INBRED MICE

Abstract

PURPOSE: The heart is a critical tissue responsible for facilitating a multitude of endurance training adaptations in aerobic capacity. Mechanisms of heart mitochondrial DNA (mtDNA) repair remain incompletely understood, and genetic susceptibility to exercise-induced mitochondrial-derived oxidative damage may be present. mtDNA damage presents as an indirect measure of mitochondrial-derived oxidative stress, while mtDNA copy number is a correlate of mitochondrial biogenesis. As two critical aspects for enhancing trainability in aerobic capacity, the purpose of this study was to characterize heart mtDNA lesions and copy number in a genetically diverse panel of male inbred mouse strains. METHODS: A genetically diverse panel of 34 inbred mouse strains were selected, and hearts of male mice (n = 184; 2 - 6 mice per strain) were removed and weighed. DNA was and a gene-specific quantitative PCR-based assay was used to measuremtDNA lesions and copy number. RESULTS: Among the strains, we found significant interstrain varitation in mtDNA lesions (range = -0.15 - 4.0 mtDNA lesions/10Kb) and copy number (range = 3682 - 111895 mtDNA copies). We observed that the wild-derived PWD/PhJ strain had the highest overall heart mtDNA lesions (PWD/PhJ = 4.31 ± 0.07 mtDNA lesions/10Kb vs all other strains = 0.25 ± 0.42 mtDNA lesions/10Kb; p<0.0001), while having the lowest overall mean mtDNA copy number (PWD/PhJ = 6,538 ± 898 mtDNA copies vs all other strains = 54,943 ± 27,085 mtDNA copies; p<0.0001). We did not find an association between mtDNA lesions or copy number with exercise capacity or heart weight. CONCLUSIONS: Our results demonstrate that there are inherent differences in heart mtDNA damage and copy number. Interestingly, the wild-derived PWD/PhJ strain had higher overall mtDNA lesions, complimented by lower mtDNA copies, possibly suggesting the hearts of this strain undergomore significant mitochondrial-derived oxidative stress (e.g. higher fission vs fusion; mitophagy) compared to others. Thus, ongoing work aims to 1) characterize markers of mitochondrial-derived oxidative stress (i.e., fission/fusion; mitophagy), 2) sequence the complete mitochondrial genome and determine levels of heteroplasmy and indels that may associate with mtDNA damage and copy number.