Effects of Triad Geometry and RyR Gating Scheme on Simulated Skeletal Muscle Sparks

Abstract

Computer models of calcium sparks have been an important tool in their investigation, especially in understanding the way how the regenerative calcium signal is initiated and terminated.The aim of the present work was to use an existing 3D model with distributed sarcoplasmic reticulum (SR) for cardiac sparks and demonstrate the effects of altered calcium release unit (CRU) geometry and ryanodine receptor (RyR) gating on the generation and termination of calcium release events in skeletal muscle.First, only the geometry of CRU was modified to match the triad structure found in skeletal muscle cells. This was achieved by arranging RyRs in double rows in the terminal cisternae (TC) membrane on each side of the T-tubule and by reducing the diameter of the T-tubule. Such a model was unable to produce the regenerative phase of the calcium spark following the stochastic opening of a single RyR. Next, the gating of RyRs was modified by shifting its calcium sensitivity to the left to mimic the baseline activity of skeletal-type RyR. This model reproduced the rising phase and the peak of the spark, but was unable to model its complete termination as observed in events measured in Saponin-permeabilized skeletal muscle fibers. Refilling of the TC had to be severely constrained or more complex gating schemes had to be introduced in order to make the termination of simulated sparks similar to that seen in the experiments.These results indicate that both the exact geometry of CRU and the gating scheme of RyR contribute to the generation and termination of localized calcium release events to a great extent and, therefore, these details have to be taken into account when their characteristics and role are examined in skeletal muscle.