Computational modelling identifies the impact of subtle anatomical variations between amphibian and mammalian skeletal muscle on spatiotemporal calcium dynamics

The physical sites of calcium entry and exit in the skeletal muscle cell are distinct and highly organised in space. It was investigated whether the highly structured spatial organisation of sites of Ca²⁺ release, uptake and action in skeletal muscle cells substantially impacts the dynamics of cytosolic Ca²⁺ handling and thereby the physiology of the cell. Hereto, the spatiotemporal dynamics of the free calcium distribution in a fast-twitch (FT) muscle sarcomere was studied using a reaction-diffusion computational model for two genotypes with known anatomical differences. A computational model of a murine FT muscle sarcomere is developed, de novo including a closed calcium mass balance to simulate spatiotemporal high stimulation frequency calcium dynamics at 35degC. Literature data on high-frequency calcium dye measurements were used as a first step towards model validation. The murine and amphibian sarcomere models were phenotypically distinct to capture known differences in positions of troponin C, actindegmyosin overlap and calcium release within the sarcomere between frog and mouse. The models predicted large calcium gradients throughout the myoplasm as well as differences in calcium concentrations near the mitochondria of frog and mouse. Furthermore, the predicted Ca²⁺ concentration was high at positions where Ca²⁺ has a regulatory function, close to the mitochondria and troponin C.