title: Quantifying inter-species differences in contractile function through biophysical modelling.
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.
authors.affiliation: Department of Biomedical Engineering, King's College London, St. Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK; Simula Research Laboratory, Martin Linges v. 17/25, Rolfsbukta 4B, Fornebu, 1364, Norway.
authors.forename: Kristin
authors.initials: K
authors.lastname: Tøndel
authors.forename: Sander
authors.initials: S
authors.lastname: Land
authors.forename: Steven A
authors.initials: SA
authors.lastname: Niederer
authors.forename: Nicolas P
authors.initials: NP
authors.lastname: Smith
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D006801:Humans; D051379:Mice; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D019209:Troponin C / Q000378:metabolism
chemical_list: D019209:Troponin C