Simulation of Ca2+ Movements within the Sarcomere of Fast-Twitch Mouse Fibers Stimulated by Action Potentials

Abstract

Ca2+ release from the sarcoplasmic reticulum (SR) of skeletal muscle takes place at the triadic junctions; following release, Ca2+ spreads within the sarcomere by diffusion. Here, we report multicompartment simulations of changes in sarcomeric Ca2+ evoked by action potentials (APs) in fast-twitch fibers of adult mice. The simulations include Ca2+ complexation reactions with ATP, troponin, parvalbumin, and the SR Ca2+ pump, as well as Ca2+ transport by the pump. Results are compared with spatially averaged Ca2+ transients measured in mouse fibers with furaptra, a low-affinity, rapidly responding Ca2+ indicator. The furaptra ΔfCaD signal (change in the fraction of the indicator in the Ca2+-bound form) evoked by one AP is well simulated under the assumption that SR Ca2+ release has a peak of 200–225 μM/ms and a FDHM of ∼1.6 ms (16°C). ΔfCaD elicited by a five-shock, 67-Hz train of APs is well simulated under the assumption that in response to APs 2–5, Ca2+ release decreases progressively from 0.25 to 0.15 times that elicited by the first AP, a reduction likely due to Ca2+ inactivation of Ca2+ release. Recovery from inactivation was studied with a two-AP protocol; the amplitude of the second release recovered to >0.9 times that of the first with a rate constant of 7 s−1. An obvious feature of ΔfCaD during a five-shock train is a progressive decline in the rate of decay from the individual peaks of ΔfCaD. According to the simulations, this decline is due to a reduction in available Ca2+ binding sites on troponin and parvalbumin. The effects of sarcomere length, the location of the triadic junctions, resting [Ca2+], the parvalbumin concentration, and possible uptake of Ca2+ by mitochondria were also investigated. Overall, the simulations indicate that this reaction-diffusion model, which was originally developed for Ca2+ sparks in frog fibers, works well when adapted to mouse fast-twitch fibers stimulated by APs.