Intrinsic Exercise Capacity and Mitochondrial DNA Lead to Opposing Vascular-Associated Risks

Abstract

Exercise capacity is a strong predictor of all-cause morbidity and mortality in humans. However, the associated hemodynamic traits that link this valuable indicator to its subsequent disease risks are numerable. Additionally, exercise capacity has a substantial heritable component and genome-wide screening indicates a vast amount of nuclear and mitochondrial DNA markers are significantly associated with traits of physical performance. A long-term selection experiment in rats confirms a divide for cardiovascular risks between low- and high-capacity runners (LCR and HCR, respectively), equipping us with a preclinical animal model to uncover new mechanisms. Here, we evaluated the LCR and HCR rat model system for differences in vascular function at the arterial resistance level. Consistent with the known divide between health and disease, we observed that LCR rats present with resistance artery and perivascular adipose tissue dysfunction compared to HCR rats that mimic qualities important for health, including improved vascular relaxation. Uniquely, we show by generating conplastic strains, that LCR males with mitochondrial DNA (mtDNA) of female HCR (LCR-mtHCR/Tol) present with improved vascular function. Conversely, HCR-mtLCR/Tol rats displayed indices for cardiac dysfunction. The outcome of this study suggests that the interplay between the nuclear genome and the maternally inherited mitochondrial genome with high intrinsic exercise capacity is a significant factor for improved vascular physiology, and animal models developed on an interaction between nuclear and mitochondrial DNA are valuable new tools for probing vascular risk factors in the offspring.

Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice

“…Videos and/or still images were captured using the Myoview data capture software (DMT, Aarhus, Denmark) and subsequently analyzed with the VasoTracker Offline Diameter Analyzer for accurate inner and outer diameter measurements [22]. From the internal and external diameter measurements in the passive conditions, structural parameters were calculated as previously described [23][24][25].…”

Effects of lactate, super-GDF9, and low oxygen tension during bi-phasic in vitro maturation on the bioenergetic profiles of mouse cumulus–oocyte complex

“…Yet, there was not a significant difference in ROS production and mitochondrial function between GV-COCs, nor in oocyte competency following IVF after CAPA-IVM. In leukocytes, the increase in non-mitochondrial OCR is attributed to the increase of inflammatory enzymes [60]. COC expansion and ovulation during oocyte maturation have been compared to an immune-like response, with similar characteristics to inflammation [61].…”

Effects of lactate, super-GDF9 and low oxygen tension during biphasic in vitro maturation on the bioenergetic profiles of mouse cumulus-oocyte-complex

“…The most significant difference between the control group and the GDF9 supplemented groups was detected at non-mitochondrial OCR, yet there was not a significant difference in ROS production and mitochondrial function between MII-COCs. In leukocytes, the increase in non-mitochondrial OCR is attributed to the increase of inflammatory enzymes [60]. COC expansion and ovulation during oocyte maturation have been compared to an immune-like response, with similar characteristics to inflammation [61].…”