Abstract 5324: Endurance Training Abolish Arrhythmogenic Calcium Leak In Cardiomyocytes From Mice With Transgenic Over-expression Of CamkiiδC
Background The cytosolic calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδC) phosphorylates several central proteins related to Ca2+ handling. Transgenic (TG) over-expression of CaMKIIδC causes depressed cardiac function, altered Ca2+ handling and increased diastolic sarcoplamic reticulum (SR) Ca2+ leak. The later may be a central trigger for delayed after depolarisation and ventricular arrhythmias in heart failure. Endurance training increases also the activity of CaMKIIδC in healthy mice, but in contrast to individuals with heart disease, this improves cardiac performance. We hypothesised that endurance training improves Ca2+ handling and reduces diastolic SR Ca2+ leak in TG mice with over-expression of CaMKIIδC and heart failure.
Methods We compared TG mice exhibiting a 3-fold increase in CaMKIIδC activity (n=8), with wild type (WT) controls (n=8). Four CaMKIIδC TG mice underwent high intensity endurance training 5 days per week over 12 weeks. Ca2+ handling and diastolic SR Ca2+ leak were measured in Fura-2AM loaded cardiomyocytes.
Results CaMKIIδC TG mice had decreased 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) and time to 50% twitch Ca2+ release was slower (25±2ms in TG vs. 15±1ms in WT, P<0.05). 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 levels of WT control. Ca2+ amplitude was also significantly increased (Fura-2AM ratio 0.15±0.02 in TG trained). Endurance training reduced diastolic SR Ca2+ leak to levels of WT control (4±2%, P<0.01). After inhibition of CaMKIIδC, by autocamtide-2-related inhibitory peptide, the increased SR Ca2+ leak in sedentary TG was abolished, while trained TG and WT control mice remained unaffected. The protein kinase inhibitor A, H89, did not affect SR Ca2+ leak in any groups.
Conclusion Endurance training improved cardiomyocyte function and Ca2+ handling in mice with TG over-expression of CaMKIIδC. Increased diastolic SR Ca2+ leak, that may trigger ventricular arrhythmias, was completely abolished after endurance training.