ABSTRACT
We previously identified two inbred rat strains divergent for treadmill aerobic running capacity (ARC), the low-performing Copenhagen (COP) and the high-performing DA rats, and used an F(2)(COPxDA) population to identify ARC quantitative trait loci (QTLs) on rat chromosome 16 (RNO16) and the proximal portion of rat chromosome 3 (RNO3). Two congenic rat strains were bred to further investigate these ARC QTLs by introgressing RNO16 and the proximal portion of RNO3 from DA rats into the genetic background of COP rats and were named COP.DA(chr 16) and COP.DA(chr 3), respectively. COP.DA(chr 16) rats had significantly greater ARC compared with COP rats (696.7 +/- 38.2 m vs. 571.9 +/- 27.5 m, P = 0.03). COP.DA(chr 3) rats had increased, although not significant, ARC compared with COP rats (643.6 +/- 40.9 m vs. 571.9 +/- 27.5 m). COP.DA(chr 16) rats had significantly greater subcutaneous abdominal fat, as well as decreased fasting triglyceride levels, compared with COP rats (P < 0.05), indicating that genes responsible for strain differences in fat metabolism are also located on RNO16. While this colocalization of QTLs may be coincidental, it is also possible that these differences in energy balance may be associated with the superior running performance of COP.DA(chr 16) consomic rats.
Subject(s)
Energy Metabolism/genetics , Phenotype , Physical Endurance/genetics , Quantitative Trait Loci , Rats/genetics , Adipose Tissue/metabolism , Analysis of Variance , Animals , Crosses, Genetic , Fasting/metabolism , Female , Genotype , Male , Microsatellite Repeats/genetics , Physical Conditioning, Animal , Rats/physiology , Species Specificity , Triglycerides/bloodABSTRACT
Our previous work found DA rats superior for intrinsic aerobic running capacity (ARC) and several cardiac function indexes compared with Copenhagen (COP) rats, and identified ARC quantitative trait loci (QTLs) on rat chromosomes 16 (RNO16) and 3 (RNO3). The purpose of this study was to use these inbred rat strains as a genetic substrate for differential cardiac gene expression to identify candidate genes for the observed ARC QTLs. RNA expression was examined globally in left ventricles of 15-wk-old DA, F1(COP x DA), and COP rats using microarrays to identify candidate genes for ARC QTLs. We identified 199 differentially expressed probe sets and determined their chromosomal locations. Six differentially expressed genes and expressed sequence tags (ESTs) mapped near ARC QTL regions, including PDZ and LIM domain 3 (Pdlim3). Differential expression of these genes/ESTs was confirmed by quantitative RT-PCR. The Ingenuity Pathways program identified 13 biological networks containing 50 (of the 199) differentially expressed probe sets and 85 additional genes. Four of these eighty-five genes mapped near ARC QTL-containing regions, including insulin receptor substrate 2 (Irs2) and acyl-CoA synthetase long-chain family member 1 (Acsl1). Most (148/199) differentially expressed probe sets showed left ventricular expression patterns consistent with the alleles exerting additive effects, i.e., F1(COP x DA) rat RNA expression was intermediate between DA and COP rats. This study identified several potential ARC QTL candidate genes and molecular networks, one of them related to energy expenditure involving Pik3r1 mRNA expression that may, in part, explain the observed strain differences in ARC and cardiac performance.
Subject(s)
Gene Expression Regulation , Heart Ventricles/pathology , Physical Conditioning, Animal , Animals , Chromosome Mapping , Cluster Analysis , Coenzyme A Ligases/metabolism , Disease Models, Animal , Expressed Sequence Tags , Gene Expression Profiling , Heart/physiology , Insulin Receptor Substrate Proteins , Intracellular Signaling Peptides and Proteins , Multigene Family , Myocardium/pathology , Oligonucleotide Array Sequence Analysis , Oligonucleotides/chemistry , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/metabolism , Protein Structure, Tertiary , RNA/chemistry , RNA/metabolism , RNA, Messenger/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , RunningABSTRACT
Aerobic capacity is a complex trait that defines the efficiency to use atmospheric oxygen as an electron acceptor in energy transfer. Copenhagen (COP) and DA inbred rat strains show a wide difference in a test for aerobic treadmill running and serve as contrasting genetic models for aerobic capacity. A genome scan was carried out on an F(2)(COP x DA) segregating population (n=224) to detect quantitative trait loci (QTLs) associated with aerobic running capacity. Linkage analysis revealed a significant QTL on chromosome 16 (lod score, 4.0). A suggestive linkage was found near the p-terminus of chromosome 3 (lod score, 2.2) with evidence of an interaction with another QTL on chromosome 16 (lod score, 2.9). All three QTLs showed a dominant mode of inheritance in which the presence of at least one DA allele was associated with a greater distance run. These results represent the first aerobic capacity QTLs identified in genetic models.
