Regulation of excitation-contraction coupling in mouse cardiac myocytes: integrative analysis with mathematical modelling

Abstract

BackgroundThe cardiomyocyte is a prime example of inherently complex biological system with inter- and cross-connected feedback loops in signalling, forming the basic properties of intracellular homeostasis. Functional properties of cells and tissues have been studied e.g. with powerful tools of genetic engineering, combined with extensive experimentation. While this approach provides accurate information about the physiology at the endpoint, complementary methods, such as mathematical modelling, can provide more detailed information about the processes that have lead to the endpoint phenotype.ResultsIn order to gain novel mechanistic information of the excitation-contraction coupling in normal myocytes and to analyze sophisticated genetically engineered heart models, we have built a mathematical model of a mouse ventricular myocyte. In addition to the fundamental components of membrane excitation, calcium signalling and contraction, our integrated model includes the calcium-calmodulin-dependent enzyme cascade and the regulation it imposes on the proteins involved in excitation-contraction coupling. With the model, we investigate the effects of three genetic modifications that interfere with calcium signalling: 1) ablation of phospholamban, 2) disruption of the regulation of L-type calcium channels by calcium-calmodulin-dependent kinase II (CaMK) and 3) overexpression of CaMK. We show that the key features of the experimental phenotypes involve physiological compensatory and autoregulatory mechanisms that bring the system to a state closer to the original wild-type phenotype in all transgenic models. A drastic phenotype was found when the genetic modification disrupts the regulatory signalling system itself, i.e. the CaMK overexpression model.ConclusionThe novel features of the presented cardiomyocyte model enable accurate description of excitation-contraction coupling. The model is thus an applicable tool for further studies of both normal and defective cellular physiology. We propose that integrative modelling as in the present work is a valuable complement to experiments in understanding the causality within complex biological systems such as cardiac myocytes.

A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII

“…) and CaMKII (Koivumaki et al . ; Edwards et al . ) regulation of mouse excitation–contraction coupling (ECC).…”

Complex restitution behavior and reentry in a cardiac tissue model for neonatal mice

“…In the last two decades, an everincreasing number of detailed biophysical models of the ionic currents in ventricular myocytes underlying action potential (AP) generation have been developed (Fink et al 2011;Winslow et al 2011). Species-specific models have been published for a number of species including guinea pig Rudy 1991, 1994), rat (Pandit et al 2001), mouse (Bondarenko et al 2004;Wang and Sobie 2008;Koivum€ aki et al 2009;Li et al 2010), and human (ten Tusscher et al 2004;Bueno-Orovio et al 2008) as it was found to be necessary to account for species-specific differences in current contributions to the AP. More recently, important developmental changes in cardiac electrophysiology of mouse myocytes have been identified (Nuss and Marban 1994;Wang et al 1996;Wetzel and Klitzner 1996;Wang and Duff 1997;Sabir et al 2008;Wang and Sobie 2008;Korhonen et al 2009;Kawamura et al 2010).…”

Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling

“…To date, one of the most influential mouse cardiomyocyte models was developed by Bondarenko and colleagues in 2004 [5]. Their model has been adapted by numerous groups to study the molecular regulation of ECC, myosin cross-bridge cycling and contraction, as well as whole-heart function [6–11]. While these modeling efforts have provided exciting new data, they contain two critical features, common in many cardiac Ca 2+ signaling models, that limit their mechanistic relevance: 1) They use a single “local [Ca 2+ ] i ” level that is identical for all RyR2s and LCCs (i.e., common pool) [5,12–22].…”