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Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity.

ABSTRACT: Rats selectively bred for inborn low capacity of running (LCR) display a series of poor health indices, whereas rats selected for high capacity of running (HCR) display a healthy profile. We hypothesized that selection of low aerobic capacity over generations leads to a phenotype with increased diastolic Ca(2+) leak that trigger arrhythmia.We used rats selected for HCR (N = 10) or LCR (N = 10) to determine the effect of inborn aerobic capacity on Ca(2+) leak and susceptibility of ventricular arrhythmia. We studied isolated Fura-2/AM-loaded cardiomyocytes to detect Ca(2+) handling and function on an inverted epifluorescence microscope. To determine arrhythmogenicity, we did a final experiment with electrical burst pacing in Langendorff-perfused hearts.Ca(2+) handling was impaired by reduced Ca(2+) amplitude, prolonged time to 50% Ca(2+) decay and reduced sarcoplasmic reticulum (SR) Ca(2+) content. Impaired Ca(2+) removal was influenced by reduced SR Ca(2+) ATP-ase 2a (SERCA2a) function and increased sodium/Ca(2+) exchanger (NCX) in LCR rats. Diastolic Ca(2) leak was 87% higher in LCR rats. The leak was reduced by CaMKII inhibition. Expression levels of phosphorylated threonine 286 CaMKII levels and increased RyR2 phosphorylation at the serine 2814 site mechanistically support our findings of increased leak in LCR. LCR rats had significantly higher incidence of ventricular fibrillation.Selection of inborn low aerobic capacity over generations leads to a phenotype with increased risk of ventricular fibrillation. Increased phosphorylation of CaMKII at serine 2814 at the cardiac ryanodine receptor appears as an important mechanism of impaired Ca(2+) handling and diastolic Ca(2+) leak that results in increased susceptibility to ventricular fibrillation.

SUBMITTER: Hoydal MA

PROVIDER: S-EPMC3980721 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity.

Høydal M A MA Stølen T O TO Johnsen A B AB Alvez M M Catalucci D D Condorelli G G Koch L G LG Britton S L SL Smith G L GL Wisløff U U

Acta physiologica (Oxford, England) 20140225 4

<h4>Aim</h4>Rats selectively bred for inborn low capacity of running (LCR) display a series of poor health indices, whereas rats selected for high capacity of running (HCR) display a healthy profile. We hypothesized that selection of low aerobic capacity over generations leads to a phenotype with increased diastolic Ca(2+) leak that trigger arrhythmia.<h4>Methods</h4>We used rats selected for HCR (N = 10) or LCR (N = 10) to determine the effect of inborn aerobic capacity on Ca(2+) leak and susce ...[more]

PMID: 24444142

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Project description:Purpose: Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and soleus gene expression we examined genome-wide gene expression in soleus muscle 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 man, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in the two groups, since accumulating evidence indicates that exercise has profound beneficial effects on the metabolic syndrome. Methods:; Soleus gene expression of both sedentary and exercise trained HCR and LCR was characterized by microarray- and gene ontology analysis. Results: Although HCR and LCR had an inborn 347% difference in running capacity, only three genes were found differentially expressed in the soleus muscle between the two groups. Up-regulation of the mitochondrial enzyme leucyl-transferRNA synthetase (LARS2) was found in the sedentary LCR. Increased expression of LARS2 has been associated with a mitochondrial DNA mutation linked to maternally inherited diabetes and mitochondrial dysfunction. In line with our findings, a growing body of evidence suggests that LCR have compromised mitochondrial function. After exercise training, 58 genes were altered in the soleus muscle of HCR, in contrast to only one in the LCR group. This suggests that animals born with different levels of fitness respond different to the same type of exercise training. Adaptations to exercise in HCR seemed to be associated with increased lipid metabolism and fatty acid elongation in the mitochondria. Also, genes associated with the peroxisomes, seemed to be central in the adaptation to exercise. Conclusion: The results indicate that (i) LCR might have mitochondrial dysfunction, which may be a contributing factor of the low inborn aerobic capacity, (ii) animals born with different levels of fitness respond different to the same exercise program. Experiment Overall Design: There are 16 samples in this study.

Project description:Purpose: Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and soleus gene expression we examined genome-wide gene expression in soleus muscle 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 man, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in the two groups, since accumulating evidence indicates that exercise has profound beneficial effects on the metabolic syndrome. Methods: Soleus gene expression of both sedentary and exercise trained HCR and LCR was characterized by microarray- and gene ontology analysis. Results: Although HCR and LCR had an inborn 347% difference in running capacity, only three genes were found differentially expressed in the soleus muscle between the two groups. Up-regulation of the mitochondrial enzyme leucyl-transferRNA synthetase (LARS2) was found in the sedentary LCR. Increased expression of LARS2 has been associated with a mitochondrial DNA mutation linked to maternally inherited diabetes and mitochondrial dysfunction. In line with our findings, a growing body of evidence suggests that LCR have compromised mitochondrial function. After exercise training, 58 genes were altered in the soleus muscle of HCR, in contrast to only one in the LCR group. This suggests that animals born with different levels of fitness respond different to the same type of exercise training. Adaptations to exercise in HCR seemed to be associated with increased lipid metabolism and fatty acid elongation in the mitochondria. Also, genes associated with the peroxisomes, seemed to be central in the adaptation to exercise. Conclusion: The results indicate that (i) LCR might have mitochondrial dysfunction, which may be a contributing factor of the low inborn aerobic capacity, (ii) animals born with different levels of fitness respond different to the same exercise program. Keywords: aerobic capacity, metabolic syndrome, soleus muscle, gene expression, metabolism

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Dataset Information

Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity.

Publications

Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity.

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