Comprehensive Simulation of Ca²⁺ Transients in the Continuum of Mouse Skeletal Muscle Fiber Types

Mag-Fluo-4 has revealed differences in the kinetics of the Ca²⁺ transients of mammalian fiber types (I, IIA, IIX, and IIB). We simulated the changes in [Ca²⁺] through the sarcomere of these four fiber types, considering classical (troponin -Tn-, parvalbumin -Pv-, adenosine triphosphate -ATP-, sarcoplasmic reticulum Ca²⁺ pump -SERCA-, and dye) and new (mitochondria -MITO-, Na⁺/Ca²⁺ exchanger -NCX-, and store-operated calcium entry -SOCE-) Ca²⁺ binding sites, during single and tetanic stimulation. We found that during a single twitch, the sarcoplasmic peak [Ca²⁺] for fibers type IIB and IIX was around 16 µM, and for fibers type I and IIA reached 10-13 µM. The release rate in fibers type I, IIA, IIX, and IIB was 64.8, 153.6, 238.8, and 244.5 µM ms^-1, respectively. Both the pattern of change and the peak concentrations of the Ca²⁺-bound species in the sarcoplasm (Tn, PV, ATP, and dye), the sarcolemma (NCX, SOCE), and the SR (SERCA) showed the order IIB ≥ IIX > IIA > I. The capacity of the NCX was 2.5, 1.3, 0.9, and 0.8% of the capacity of SERCA, for fibers type I, IIA, IIX, and IIB, respectively. MITO peak [Ca²⁺] ranged from 0.93 to 0.23 µM, in fibers type I and IIB, respectively, while intermediate values were obtained in fibers IIA and IIX. The latter numbers doubled during tetanic stimulation. In conclusion, we presented a comprehensive mathematical model of the excitation-contraction coupling that integrated most classical and novel Ca²⁺ handling mechanisms, overcoming the limitations of the fast- vs. slow-fibers dichotomy and the use of slow dyes.