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.; Stølen, T.; Johnsen, A.; Alvez, M.; Catalucci, D.; Condorelli, G.; Koch, L.; Britton, S.; Smith, G.; Wisløff, U.

doi:10.1111/apha.12238

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 Ca2+ 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 Ca2+ leak and susceptibility of ventricular arrhythmia. We studied isolated FURA2/AM loaded cardiomyocytes to detect Ca2+ -handling and function on an inverted epi-fluorescence microscope. To determine arrhythmogenicity we did a final experiment with electrical burst pacing in Langendorff perfused hearts. RESULTS: Ca2+ -handling was impaired by reduced Ca2+ amplitude, prolonged time to 50% Ca2+ decay, and reduced sarcoplasmic reticulum (SR) Ca2+ -content. Impaired Ca2+ removal was influenced by reduced SR Ca2+ ATP-ase 2a (SERCA2a) function and increased sodium/Ca2+ -exchanger (NCX) in LCR rats. Diastolic Ca2 leak was 87% higher in LCR rats. The leak was reduced by CaMKII inhibition. Expression levels of phosphorylated theorine-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 Ca2+ handling and diastolic Ca2+ leak that results in increased susceptibility to ventricular fibrillation.

Titolo:	Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity
Autori:	M. Høydal T. Stølen A. Johnsen M. Alvez D. Catalucci CONDORELLI, Gianluigi L. Koch S. Britton G. Smith U. Wisløff mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2014
Rivista:	ACTA PHYSIOLOGICA
Handle:	http://hdl.handle.net/11699/6628
Appare nelle tipologie:	1.1 Articolo in rivista

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http://hdl.handle.net/11699/6628

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