Key result
A spatially detailed numerical model accurately reproduced junctional sarcoplasmic reticulum Ca2+ kinetics in rat cardiomyocytes, showing that kinetics are determined by total release flux rather than RyR2 positioning.
Why the study?
The properties of cardiac sarcoplasmic reticulum Ca2+ have not yet been fully determined, particularly in rats and mice.
A novel computational model of rat cardiomyocyte SR Ca2+ handling demonstrates that total RyR2 release flux and fluorescence dye kinetics are critical determinants of apparent jSR Ca2+ depletion.
Refines jSR Ca2+ modeling in rodent myocytes; leaves open clinical translation pending experimental validation.
The sarcoplasmic reticulum (SR) primarily serves as the intracellular Ca2+ store in cardiac myocytes, mediating cellular function under cardiac physiology and diseases. However, the properties of cardiac SR Ca2+ have not yet been fully determined, particularly in rats and mice, which are the most commonly used experimental species in studies on cardiac physiology and diseases. Here, we developed a spatially detailed numerical model to deduce Ca2+ movements inside the junctional SR (jSR) cisternae of rat cardiomyocytes. Our model accurately reproduced the jSR Ca2+ kinetics of local and global SR Ca2+ releases reported in a recent experimental study. With this model, we revealed that jSR Ca2+ kinetics was mostly determined by the total release flux via type 2 ryanodine receptor (RyR2) channels but not by RyR2 positioning. Although Ca2+ diffusion in global SR was previously reported to be slow, our simulation demonstrated that Ca2+ diffused very quickly inside local jSR cisternae and the decrease in the diffusion coefficient resulted in a significant reduction of jSR Ca2+ depletion amplitude. Intracellular Ca2+ was typically experimentally detected with fluorescence dye. Our simulation revealed that when the dynamical characteristics of fluorescence dye exerted a minimal effect on actual Ca2+ mobility inside jSR, the reaction rate of the dye with Ca2+ could significantly affect apparent jSR Ca2+ kinetics. Therefore, loading a chemical fluorescence dye with fast kinetics, such as Fluo-5N, into SR is important for Ca2+ measurement inside SR. Overall, our model provides new insights into deciphering Ca2+ handling inside nanoscopic jSR cisternae in rat cardiomyocytes.
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Su et al. (2024) studied Cardiac physiology (rat cardiomyocytes). Spatially detailed numerical model of jSR Ca2+ movements was evaluated on jSR Ca2+ kinetics (amplitude and full duration at half maximum). A spatially detailed numerical model accurately reproduced junctional sarcoplasmic reticulum Ca2+ kinetics in rat cardiomyocytes, showing that kinetics are determined by total release flux rather than RyR2 positioning.
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