Artificial Selection for Whole Animal Low Intrinsic Aerobic Capacity Co-Segregates with Hypoxia-Induced Cardiac Pump Failure

Nathan J Palpant,Wang Wang,Dewayne Townsend,Lauren G Koch,Michael L Szatkowski,Steven L Britton,Fikru B Bedada,Joseph M Metzger,Jose A L Calbet

doi:10.1371/journal.pone.0006117

Abstract

Oxygen metabolism is a strong predictor of the general health and fitness of an organism. In this study, we hypothesized that a divergence in intrinsic aerobic fitness would co-segregate with susceptibility for cardiovascular dysfunction. To test this hypothesis, cardiac function was assessed in rats specifically selected over nineteen generations for their low (LCR) and high (HCR) intrinsic aerobic running capacity. As an integrative marker of native aerobic capacity, run time to exhaustion between LCR and HCR rats had markedly diverged by 436% at generation nineteen of artificial selection. In vivo assessment of baseline cardiac function by echocardiography and catheter-based conductance micromanometry showed no marked difference in cardiac performance. However, when challenged by exposure to acute hypoxia, cardiac pump failure occurred significantly earlier in LCR rats compared to HCR animals. Acute cardiac decompensation in LCR rats was exclusively due to the development of intractable irregular ventricular contractions. Analysis of isolated cardiac myocytes showed significantly slower sarcomeric relaxation and delayed kinetics of calcium cycling in LCR myocytes compared to HCR myocytes. This study also revealed that artificial selection for low native aerobic capacity is a novel pathologic stimulus that results in myosin heavy chain isoform switching in the heart as shown by increased levels of β-MHC in LCR rats. Together, these results provide evidence that alterations in sub-cellular calcium handling and MHC isoform composition are associated with susceptibility to compensatory cardiac remodeling and hypoxia induced pump failure in animals with low intrinsic aerobic capacity.

Highlights

The prevalence of metabolic syndrome has come to be regarded as a window into the general health of a population [1]
The current study used rats selected for 19 generations which showed further divergence in native aerobic running capacity between low capacity runners (LCR) and high capacity runners (HCR) rats
The results of this study reveal an increased susceptibility to hypoxia in LCR rats consistent with the finding that risk factors for cardiac disease and, deficiencies in cardiac calcium homeostasis segregate with aerobic running capacity

Summary

Introduction

The prevalence of metabolic syndrome has come to be regarded as a window into the general health of a population [1]. Studies in the U.S have shown that nearly a quarter of the population (an estimated 47 million people) have metabolic syndrome [3]. Cross-sectional and prospective studies have found that levels of physical activity and fitness are inversely related to the prevalence of metabolic syndrome [5]. These and other studies suggest a link between intrinsic aerobic capacity, based on genetic and environmental influences, and complex disease states [5,6,7,8,9]

Methods

Results

Discussion

Conclusion