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lüll Synchrony of cardiomyocyte Ca(2+) release is controlled by T-tubule organization, SR Ca(2+) content, and ryanodine receptor Ca(2+) sensitivity Oyehaug L; Loose KO; Jolle GF; Roe AT; Sjaastad I; Christensen G; Sejersted OM; Louch WEBiophys J 2013[Apr]; 104 (8): 1685-97Recent work has demonstrated that cardiomyocyte Ca(2+)release is desynchronized in several pathological conditions. Loss of Ca(2+) release synchrony has been attributed to t-tubule disruption, but it is unknown if other factors also contribute. We investigated this issue in normal and failing myocytes by integrating experimental data with a mathematical model describing spatiotemporal dynamics of Ca(2+) in the cytosol and sarcoplasmic reticulum (SR). Heart failure development in postinfarction mice was associated with progressive t-tubule disorganization, as quantified by fast-Fourier transforms. Data from fast-Fourier transforms were then incorporated in the model as a dyadic organization index, reflecting the proportion of ryanodine receptors located in dyads. With decreasing dyadic-organization index, the model predicted greater dyssynchrony of Ca(2+) release, which exceeded that observed in experimental line-scan images. Model and experiment were reconciled by reducing the threshold for Ca(2+) release in the model, suggesting that increased RyR sensitivity partially offsets the desynchronizing effects of t-tubule disruption in heart failure. Reducing the magnitude of SR Ca(2+) content and release, whether experimentally by thapsigargin treatment, or in the model, desynchronized the Ca(2+) transient. However, in cardiomyocytes isolated from SERCA2 knockout mice, RyR sensitization offset such effects. A similar interplay between RyR sensitivity and SR content was observed during treatment of myocytes with low-dose caffeine. Initial synchronization of Ca(2+) release during caffeine was reversed as SR content declined due to enhanced RyR leak. Thus, synchrony of cardiomyocyte Ca(2+) release is not only determined by t-tubule organization but also by the interplay between RyR sensitivity and SR Ca(2+) content.|*Calcium Signaling[MESH]|Animals[MESH]|Caffeine/pharmacology[MESH]|Calcium Channel Blockers/pharmacology[MESH]|Calcium/*metabolism[MESH]|Cytosol/metabolism[MESH]|Female[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Models, Biological[MESH]|Myocardial Infarction/metabolism/pathology[MESH]|Myocytes, Cardiac/*metabolism/ultrastructure[MESH]|Ryanodine Receptor Calcium Release Channel/drug effects/*metabolism[MESH]|Sarcolemma/metabolism/*ultrastructure[MESH]|Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism[MESH]|Sarcoplasmic Reticulum/*metabolism[MESH]|Thapsigargin/pharmacology[MESH] |