Effect of chromosome substitution on intrinsic exercise capacity in mice.

Sean M Courtney,Michael P Massett

doi:10.12688/f1000research.3-9.v2

Sean M Courtney, Michael P Massett

Open Access

https://doi.org/10.12688/f1000research.3-9.v2

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Abstract

Previous research identified a locus on Chromosome 14 as an important regulator of endurance exercise capacity in mice. The aim of this study was to investigate the effect of chromosome substitution on intrinsic exercise capacity and identify quantitative trait loci (QTL) associated with exercise capacity in mice. Mice from a chromosome substitution strain (CSS) derived from A/J and C57Bl/6J (B6), denoted as B6.A14, were used to assess the contribution of Chromosome 14 to intrinsic exercise capacity. All mice performed a graded exercise test to exhaustion to determine exercise capacity expressed as time (min) or work (kg·m). Exercise time and work were significantly greater in B6 mice than B6.A14 and A/J mice, indicating the presence of a QTL on Chromosome 14 for exercise capacity. To localize exercise-related QTL, 155 B6.A14 x B6 F 2 mice were generated for linkage analysis. Suggestive QTL for exercise time (57 cM, 1.75 LOD) and work (57 cM, 2.08 LOD) were identified in the entire B6.A14 x B6 F 2 cohort. To identify putative sex-specific QTL, male and female F 2 cohorts were analyzed separately. In males, a significant QTL for exercise time (55 cM, 2.28 LOD) and a suggestive QTL for work (55 cM, 2.19 LOD) were identified. In the female cohort, no QTL was identified for time, but a suggestive QTL for work was located at 16 cM (1.8 LOD). These data suggest that one or more QTL on Chromosome 14 regulate exercise capacity. The putative sex-specific QTL further suggest that the genetic architecture underlying exercise capacity is different in males and females. Overall, the results of this study support the use of CSS as a model for the genetic analysis of exercise capacity. Future studies should incorporate the full panel of CSS using male and female mice to dissect the genetic basis for differences in exercise capacity.

Highlights

Cardiorespiratory fitness measured during a graded exercise test is inversely related to the relative risk of cardiovascular disease1,2
When exercise capacity was expressed as work, A/J and B6.A14 strains were significantly different from B6 (P < 0.0001), with mice from both strains performing less work than B6 mice (Figure 1B)
The purpose of the current study was to determine the role of mouse Chromosome 14 (Chr 14) in the genetic regulation of exercise capacity and to fine map this chromosome to identify quantitative trait loci (QTL) for exercise capacity

Summary

Introduction

Cardiorespiratory fitness measured during a graded exercise test is inversely related to the relative risk of cardiovascular disease. One common approach has been to screen multiple rodent strains for exercise capacity, followed by quantitative trait loci (QTL) analyses to identify loci linked to exercise capacity. This approach has been used to identify QTL for exercise capacity in rats and mice. Research from our laboratory previously identified significant and suggestive QTL on several chromosomes that may house candidate genes that influence variation in exercise capacity. Research from our laboratory previously identified significant and suggestive QTL on several chromosomes that may house candidate genes that influence variation in exercise capacity13,14 These identified regions overlap with other mouse and human QTL, suggesting that these regions and/or genes are conserved among species. The present study focused on characterizing the role of Chr 14 in regulating intrinsic exercise capacity

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