Quantifying inter‐species differences in contractile function through biophysical modelling

Abstract

Key pointsr To facilitate translation of data from animal models into clinical applications, it is important to analyse and quantify the differences and relevance of specific physiological mechanisms between species.r We propose a novel approach for the quantification of inter-species differences in terms of biophysical model parameters and apply this to elucidate the differences in cardiac contraction mechanisms between mouse, rat and human.r Our results indicate that the parameters related to the sensitivity and cooperativity of calcium binding to troponin C and the activation and relaxation rates of tropomyosin/crossbridge binding kinetics differ most significantly between mouse, rat and human.r Our results predict crossbridge binding to be slowest in human and fastest in mouse.Abstract Animal models and measurements are frequently used to guide and evaluate clinical interventions. In this context, knowledge of inter-species differences in physiology is crucial for understanding the limitations and relevance of animal experimental assays for informing clinical applications. Extensive effort has been put into studying the structure and function of cardiac contractile proteins and how differences in these translate into the functional properties of muscles. However, integrating this knowledge into a quantitative description, formalising and highlighting inter-species differences both in the kinetics and in the regulation of physiological mechanisms, remains challenging. In this study we propose and apply a novel approach for the quantification of inter-species differences between mouse, rat and human. Assuming conservation of the fundamental physiological mechanisms underpinning contraction, biophysically based computational models are fitted to simulate experimentally recorded phenotypes from multiple species. The phenotypic differences between species are then succinctly quantified as differences in the biophysical model parameter values. This provides the potential of quantitatively establishing the human relevance of both animal-based experimental and computational models for application in a clinical context. Our results indicate that the parameters related to the sensitivity and cooperativity of calcium binding to troponin C and the activation and relaxation rates of tropomyosin/crossbridge binding kinetics differ most significantly between mouse, rat and human, while for example the reference tension, as expected, shows only minor differences between the species. Hence, while confirming expected inter-species differences in calcium sensitivity due to large differences in the observed calcium transients, our results also indicate more unexpected differences in the cooperativity mechanism. Specifically, the decrease in the unbinding rate of calcium to troponin C with increasing active tension was much lower for mouse than for rat and human. Our results also predicted crossbridge binding to be slowest in human and fastest in mouse.

A Spatially Detailed Model of Isometric Contraction Based on Competitive Binding of Troponin I Explains Cooperative Interactions between Tropomyosin and Crossbridges

“…The last 500 ms of the human tension transients are not shown, as force is very low throughout. These results were driven by fixed calcium transients shown in panel B, based on recent data in mouse [ 66 ] and rat (see S1 Text [ 67 , 68 ]) measured at 37°C and 6 Hz, and data from Coppini et al [ 69 ] (see S1 Text [ 70 ]). Two sets of results are shown, corresponding to a constant crossbridge unbinding rate ( q = 1 in Eq 22 ) and a crossbridge unbinding rate that is variable, modified by the average difference in free energy for the tropomyosin deformation ( q = 0.5 in Eq 22 )…”

Anatomically accurate high resolution modeling of human whole heart electromechanics: A strongly scalable algebraic multigrid solver method for nonlinear deformation

“…Therefore, the number of states in the combined state vector w is 58, which is one less than the sum of the number of states of the GPB state vector η (54 states) and the LN state vector ζ (5 states). Parameters of the GPB model were left unaltered whereas parameters of the LN model were adapted to give human myocardium tension transients when coupled to the GPB calcium transient [111] (see Tab. 1).…”

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

“…Specifically, although data for isometric twitch contractile function exists [53,44] and has been used to parametrize contraction models [64,36], comprehensive data sets for human myocyte contractile function which characterize length-and velocity-dependence of tension generation are not available. In addition, many measurements across species are taken at lower temperatures, including measurements of human myofibrils [54], which limits their application for explaining whole organ contractile function.…”

“…However, there remains a deficit of human biophysical models of tension generation which can be embedded within models of whole organ contraction. Currently whole organ frameworks typically rely on phenomenological models of cellular function [30,58] or models preferentially fitted to animal data [64].…”