The dynamics of Ca2+ within the sarcoplasmic reticulum of frog skeletal muscle. A simulation study

Abstract

In skeletal muscle, Ca²⁺ release from the sarcoplasmic reticulum (SR) triggers contraction. In this study we develop a two compartment model to account for the Ca²⁺ dynamics in frog skeletal muscle fibers. The two compartments in the model correspond to the SR and the cytoplasm, where the myofibrils are placed. We use a detailed model for the several Ca²⁺ binding proteins in the cytoplasm in line with previous models. As a new feature, Ca²⁺ binding sites within the SR, attributed to calsequestrin, are modeled based on experimentally obtained properties. The intra SR Ca²⁺ buffer shows cooperativity, well represented by a Hill equation with parameters that depend on the initial [Ca²⁺] in the SR ([Ca²⁺]_SR). The number of total sites as well as the [Ca²⁺]_SR of half saturation are reduced as the resting [Ca²⁺]_SR is reduced, on the other hand the Hill number is not changed. The buffer power remained roughly constant. The release process is activated by a voltage dependent mechanism that increases the Ca²⁺ permeability of the SR. We use the permeability time course and amplitude experimentally obtained during a voltage clamp pulse to drive the simulations. This model successfully reproduces the SR and cytoplasmic transients observed. Additionally, we simulate [Ca²⁺] _SR transients in the case of high concentration of extrinsic Ca²⁺ buffers added to the cytoplasm to explore what properties of the permeability are necessary to account for the experimentally observed [Ca²⁺]_SR transients. The main novelty of the model, the intra SR Ca²⁺ buffer, is crucial for reproducing the experimental observations and it would be of use in future theoretical studies of excitation contraction coupling in skeletal muscle.

Keywords: Calcium signaling; Excitation contraction coupling; Sarcoplasmic reticulum; Skeletal muscle.