Multiscale Modelling of the Effects of Temperature on Cardiac Twitches

Abstract

Functional changes in cardiac muscle, caused by mutations in sarcomere proteins, are significant for understanding cardiac pathophysiology. Experimental investigations of mechanical responses in cardiac tissue, especially in humans, are limited due to challenges in obtaining suitable samples. Trabeculae from transgenic rodent models serve as a common experimental model for studying cardiac function. However, differences in temperature between experimental settings and physiological conditions, as well as differences in myosin α and β isoform content, can complicate the interpretation and translation of findings from rodents to humans. To bridge this gap, we present a novel methodology utilizing the MUSICO computational simulation platform for multiscale modeling of cardiac twitch contractions. MUSICO integrates crossbridge cycling, calcium regulation of thin and thick filaments, explicit 3D sarcomere geometry, and species-specific mixtures of myosin isoforms. In this study, we quantitatively estimated the impact of temperature variations on twitch transients in rat trabeculae using MUSICO simulations. Model predictions were compared with a consistent set of experimental data from rat trabeculae. Our results demonstrated that the temperature of the experiments plays a significant role in force generation during cardiac muscle twitch, since it affects intracellular calcium concentrations, but also influences several crossbridge cycle kinetic rates which had to be adjusted in simulations for accurate predictions of twitch responses. By accounting for species-specific physiological variations and the temperature sensitivity of cardiac responses, this approach offers insights into a more comprehensive understanding of cardiac dynamics, ultimately leading to the prediction of human cardiac muscle responses under physiological conditions. Through improved predictive capabilities, MUSICO will open new opportunities for the development of novel therapeutics and treatments targeting cardiomyopathies.