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

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 Δf_CaD 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). Δf_CaD 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 Δf_CaD during a five-shock train is a progressive decline in the rate of decay from the individual peaks of Δf_CaD. 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.