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

Acta Physiol (Oxf). 2014 Apr;210(4):854-64. doi: 10.1111/apha.12238. Epub 2014 Feb 25.

Abstract

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: aerobic capacity; arrhytmia; calcium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis
  • Animals
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / physiopathology*
  • Calcium / metabolism
  • Mitochondria / physiology
  • Myocytes, Cardiac / physiology
  • Physical Conditioning, Animal / physiology*
  • Rats
  • Rats, Inbred Strains
  • Running / physiology*
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / physiology
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism

Substances

  • Ryanodine Receptor Calcium Release Channel
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium