Endurance Training Abolish Arrhythmogenic Ca2+ Leak In Cardiomyocytes From Mice Over-expressing CaMKII

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Background: Transgenic (TG) over-expression of calcium/calmodulin-dependent protein kinase IIδC (CaMKIIδC) causes depressed cardiac function, altered Ca2+ handling and increased diastolic sarcoplamic reticulum (SR) Ca2+ leak. The latter may trigger ventricular arrhythmias in heart failure. Aim of the study was to investigate the effects of endurance training on Ca2+ handling and diastolic SR Ca2+ leak in TG mice with over-expression of CaMKIIδC.Methods: Four CaMKIIδC TG mice underwent high intensity endurance training 5 days per week over 12 weeks and were compared to TG sedentary and wild type (WT). Ca2+ handling, diastolic SR Ca2+ leak, t-tubule density and SR Ca2+ release synchronicity were measured in single cardiomyocytes.Results: TG mice had depressed cardiomyocyte shortening (3.3±1.8% in TG vs. 6.2±1.2% in WT, P<0.01). Ca2+ transient amplitude were lower (Fura-2AM ratio in TG was 0.09±0.03 vs. 0.18±0.02 in WT, P<0.01). SR Ca2+ leak over the RyR was significantly larger in TG mice (19±3% of total SR Ca2+ vs. 5±2% in WT, P<0.01). Endurance training restored cardiomyocyte shortening (5.9±1.3% in TG trained) to WT level. Ca2+ amplitude was also significantly increased (Fura-2AM ratio 0.15±0.02 in TG trained). Endurance training reduced diastolic SR Ca2+ leak to WT levels (4±2%, P<0.01 vs. TG). CaMKIIδC inhibition and not PKA inhibition normalized SR Ca2+ leak in TG and was comparable to TG endurance trained and WT. TG had both reduced t-tubule density (13±4% in TG vs. 18±2% in WT, P<0.05) and reduced SR Ca2+ release synchronicity (P<0.05), whereas t-tubule density and SR Ca2+ release synchronicity in endurance trained TG were comparable to WT.Conclusion: Endurance training improved cardiomyocyte function and Ca2+ handling in mice with TG over-expression of CaMKIIδC. Increased diastolic SR Ca2+ leak, t-tubule density and SR Ca2+ release synchronicity was normalized after endurance training.