AUTHOR=Kim Haedong , Yang Hui , Ednie Andrew R. , Bennett Eric S. 

TITLE=Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes

JOURNAL=Frontiers in Physiology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.816651

DOI=10.3389/fphys.2022.816651

ISSN=1664-042X

ABSTRACT=Dilated cardiomyopathy (DCM) is the third most common cause of heart failure and the primary reason for heart transplantation; upward of 70\% of DCM cases are considered idiopathic. Our in-vitro experiments showed that reduced hybrid/complex N-glycosylation in mouse cardiomyocytes is linked with DCM. Further, we observed direct effects of reduced N-glycosylation on K\textsubscript{v} gating. However, it is difficult to rigorously determine the effects of glycosylation on K\textsubscript{v} activity, because there are multiple K\textsubscript{v} isoforms in cardiomyocytes contributing to the cardiac excitation. Due to complex functions of K\textsubscript{v} isoforms, only the sum of K\textsuperscript{+} currents (I\textsubscript{Ksum}) can be recorded experimentally and decomposed later using exponential fitting to estimate component currents such as I\textsubscript{Kto}, I\textsubscript{Kslow}, I\textsubscript{Kss}. However, such estimation cannot adequately describe glycosylation effects and K\textsubscript{v} mechanisms. Here, we propose a framework of simulation modeling of K\textsubscript{v} kinetics in mouse ventricular myocytes and model calibration using the in-vitro data under normal and reduced glycosylation conditions through ablation of the Mgat1 gene (i.e., Mgat1KO). Calibrated models facilitate the prediction of K\textsubscript{v} characteristics at different voltages that are not directly observed in the in-vitro experiments. A model calibration procedure is developed based on the genetic algorithm. Experimental results show that, in the Mgat1KO group, both I\textsubscript{Kto} and I\textsubscript{Kslow} densities are shown to be significantly reduced and the rate of I\textsubscript{Kslow} inactivation is much slower. The proposed approach has strong potential to couple simulation models with experimental data for gaining a better understanding of glycosylation effects on K\textsubscript{v} kinetics.