Peak Ca2+ release in between central region of U- and W-shaped transient: {p,0.05. Data are presented as mean6SD. n = 19 cells for LCR and 16 cells for HCR. doi:10.1371/journal.pone.0076568.get al. [13] who found cells with W-shaped Ca2+ transients to have significantly faster recovery of systolic Ca2+ amplitude after complete depletion of Ca2+ by caffeine application. At increasing frequencies the functional consequences of delayed central Ca2+ rise in LCR rats will be even more pronounced because of the increased demand of rapid initiation of Ca2+ induced Ca2+ release. Therefore, we suggest an association between the observed differences in spatio-temporal characteristics of Ca2+-signal and the observed differences in atrial myocyte systolic performance due to the fact that slow rise in Ca2+ release may limit synchronous contractile activation, especially at high cardiac frequencies [14].increased in the LCR rats. Importantly, this suggests a deleterious signaling induced by contrasting for low aerobic capacity.ConclusionsThis study report for the first time that contrasting for low or high aerobic capacity leads to diverse functional and structural remodeling of atrial myocytes. Compared to rats with high aerobic capacity we found that low aerobic capacity in LCR rats was associated with reduced atrial myocyte contractility and diastolic relaxation that were associated with impaired Ca2+-handling. Reduced systolic Ca2+ amplitude in LCR rats was associated with reduced ability to initiate Ca2+ release from the SR that probably is caused by a less Duocarmycins Accession developed T-tubule network. Furthermore, low aerobic capacity in LCR rats led to an increased diastolic SR Ca2+ leak over the RyR2, which has been linked to cardiac arrhythmias in several RORĪ± review studies on left ventricular myocytes. Our study therefore suggests that low aerobic capacity may lead to negative signaling in atrial myocytes with defective properties of Ca2+ handling that is not only negative for atrial function but also may cause a cellular substrate that is more prone for triggering of atrial arrhythmias. It is likely that the improved cardiomyocyte function and Ca2+ handling associated with high aerobic capacity has a positive effect during increased workload of the atria. It is furthermore tempting to speculate that the positive adaptations in the atrial cellular mechanisms may protect against atrial dysfunction such as atrial fibrillation.Increased Diastolic SR Ca2+ LeakThe observation of increased diastolic SR Ca2+ leak in atrial myocytes is interesting since this is the first report showing that low aerobic capacity leads to a cellular substrate that may be more prone to triggering of atrial arrhythmias. Several studies on ventricle cardiomyocytes [224] and also from patients with atrial fibrillation [25] have shown that increased RyR2 Ca2+ leak from the SR during diastole is a potent trigger for uncontrolled electrical activity that may cause spontaneous contractions and arrhythmias. On this basis several novel Ca2+ release RyR2stabilizing drugs have been proposed [26]. Phosphorylation of serine 22814 at the RyR2 by CaMKII is a well-documented cause of increased Ca2+ leak [17,22,27]. Although further studies including higher number of animals are necessary to elucidate the mechanism involved in the regulation of Ca2+ leak, our data indicates that RyR2 serine-2814 phosphorylation is apparentlyPLOS ONE | plosone.orgAtrial Myocyte Ca2+ Handling and Aerobic CapacityAuthor Contributions.
