Aerobic capacity-dependent differences in cardiac gene expression

Abstract

Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and cardiac gene expression we examined genome-wide gene expression in hearts of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in human, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in these animals. Left ventricle gene expression of both sedentary and exercise-trained HCR and LCR was characterized by microarray and gene ontology analysis. Out of 28,000 screened genes, 1,540 were differentially expressed between sedentary HCR and LCR. Only one gene was found differentially expressed by exercise training, but this gene had unknown name and function. Sedentary HCR expressed higher amounts of genes involved in lipid metabolism, whereas sedentary LCR expressed higher amounts of the genes involved in glucose metabolism. This suggests a switch in cardiac energy substrate utilization from normal mitochondrial fatty acid ␤-oxidation in HCR to carbohydrate metabolism in LCR, an event that often occurs in diseased hearts. LCR were also associated with pathological growth signaling and cellular stress. Hypoxic conditions seemed to be a common source for several of these observations, triggering hypoxia-induced alterations of transcription. In conclusion, inborn high vs. low aerobic capacity was associated with differences in cardiac energy substrate, growth signaling, and cellular stress. metabolic syndrome; metabolism; hypoxia; V O2max; hypertrophy ALTHOUGH MAXIMAL OXYGEN UPTAKE (V O 2max ) is statistically linked with cardiovascular mortality (23, 36), the mechanistic nature of this association is unknown and difficult to explore in humans. Specifically, it is well defined that the continuum of heart function is linearly related with the level of V O 2max (39). Within the gene-environment interactions, inheritance may account for as much as 70% of the variation in aerobic capacity in human (7). Hence, genetic predisposition and inborn aerobic capacity are likely to contribute toward cardiovascular disease and mortality.Rats with different inborn running capacities have been artificially selected over generations to generate strains with genetically determined high or low intrinsic capacity (25). The evolved strains of high capacity runners (HCR) and low capacity runners (LCR) have a 30% difference in V O 2max (17). Selecting for low running capacity also resulted in accumulation of risk factors that predispose to cardiovascular disease. That is, LCR have features of the metabolic syndrome, whereas HCR show an athletic phenotype with markedly better cardiac and vascular function relative to LCR (17, 52). These models were generated expressly for efficient and invasive evaluation of cardiometabolic disease that can lea...

Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function

“…These findings raise the possibility that impaired microvascular perfusion is a contributing factor to the cardiac phenotype associated with an inherited low capacity for exercise. Previous proteomic and array studies (3,4) suggested that LCR may exhibit a predisposition for LV remodeling, but those studies focused on older animals (30 -50 wk of age). Confirmation of morphological changes specifically on LV histology, protein content, or gene expression using real-time PCR or other semiquantitative approaches was not available.…”

“…Recent work has now suggested that more mature LCR rats (ϳ30 wk of age) exhibit upregulated cardiac collagen deposition (6). Following enzymatic isolation, cardiomyocytes from older LCR also tend to be shorter and wider than those from their HCR counterparts (4,19). Here we demonstrate that the onset of cardiac fibrosis in the LCR phenotype occurs considerably earlier and is evident already by 12 wk.…”

“…Modest but significant impairments in myocardial systolic and diastolic function are observed in cardiomyocytes isolated from LCR compared with HCR rats (49). Presumably, these differences are attributable to abnormalities in myocardial mitochondrial protein content (3), similar to those previously seen in skeletal muscle in LCR rats, in addition to a relative myocardial downregulated expression of genes controlling lipid versus glucose as an energy substrate (4).…”

Metabolic rates associated with membrane fatty acids in mice selected for increased maximal metabolic rate

“…Mechanistically, elevated amounts of 18:2 n-6, 20:4 n-6, and 22:6 n-3 fatty acids in muscle membranes might have modulated the decreased amounts of free fatty acids and intra-muscular triacylglycerol fatty acids in high-MMR mice (Wone et al 2011). Likewise, a gene expression study of rat heart muscle from Koch and Britton’s (2001) divergent selection experiment on exercise capacity showed that high-capacity runners switched toward fatty acid oxidation metabolism, whereas low-capacity runners switched toward glucose-based metabolism (Bye et al 2008). Hence, one might expect that those fatty acids that are involved in fatty acid metabolism to be present in greater percentages in membranes of cardiac tissues of high-capacity runners compared with low-capacity runners.…”

Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction

“…Thus, LCR rats exhibit metabolic and cardiovascular phenotypes (i.e., overweight, insulin resistance, elevated blood pressure, and dyslipidemia). Cardiac gene expression profiling indicated the differential expression of numerous genes, especially those related to lipid and glucose metabolism (8). Nonetheless, the functional consequences of differential gene expression in female and male LCR and HCR hearts have not been examined in detail.…”