Effects of GM regulation during Phase I and Phase II on the membrane potential depolarization and t-system K+ concentration during trains of APs. (A) Representative experimental recordings of the membrane potential from a muscle fibers that was repeatedly activated to fire 49 APs at 15 Hz every 7 s. Recordings show the first (left), the 40th (middle), and the 80th (right) AP train. To highlight the regulation of GM during AP firing, the membrane potential responses (underlined above) to the small current injections in between the AP trains have been highlighted below. As previously reported (Pedersen et al., 2009a), the onset of AP firing leads to a reduction in GM, as shown by an enlarged membrane potential deflection during the current injection (Phase I), whereas prolonged AP firing leads to a marked rise in GM (Phase II), as revealed by a reduced membrane potential deflection. To determine the effect of such GM regulation in active muscle fiber on the depolarization of the resting membrane potential during the AP trains, the membrane potential before AP firing was subtracted from the potential as recorded 55 ms after every AP. (B) The average change in resting membrane potential during the AP trains during control conditions (first AP train), during Phase I (40th train), and during Phase II (80th train). (C) GM during AP firing as originally reported by Pedersen et al. (2009a). (D) Changes in the composite conductances for K+ (GK) and Cl− (GCl) that underlie the changes in GM in C. (E) The depolarization of the resting membrane potential during the AP trains was determined in simulated AP trains in a similar way that this depolarization was assessed in the experimental recordings in B. (F) The K+ concentration in the deepest t-system compartment during the simulation of AP trains during the three conditions. (G) The magnitude of depolarization of the resting membrane potential during simulated 15-Hz trains (circles) and the corresponding t-system K+ in the deepest t-system shell (triangles) for a range of Cl− membrane permeabilities. Typical values for Cl− permeabilities for the three conditions have been indicated.