Quantifying inter-species differences in contractile function through biophysical modelling.

Area of Science:

• Physiology
• Biophysics
• Computational Biology

Background:

• Animal models are vital for clinical intervention evaluation, necessitating understanding inter-species physiological differences.
• Quantifying these differences in cardiac contractile mechanisms remains a challenge.

Purpose of the Study:

• To develop and apply a novel computational approach for quantifying inter-species differences in cardiac contractile proteins.
• To establish the human relevance of animal models by comparing mouse, rat, and human cardiac function.

Main Methods:

• Utilized biophysically based computational models fitted to experimental data from multiple species.
• Quantified inter-species phenotypic variations as differences in biophysical model parameter values.

Main Results:

• Significant inter-species differences were identified in calcium binding sensitivity and cooperativity to troponin C.
• Activation and relaxation rates of tropomyosin/crossbridge binding kinetics varied significantly, with human slowest and mouse fastest.
• Unexpected differences in calcium unbinding rates to troponin C were observed, particularly in mice.

Conclusions:

• The novel computational approach quantitatively distinguishes inter-species cardiac functional differences.
• Results highlight significant variations in calcium handling and crossbridge kinetics, impacting the translational relevance of animal models.
• Findings provide a framework for assessing the clinical applicability of animal experimental and computational models.