Regulation of force dynamics in fast twitch muscle

Several regulatory steps controlling skeletal muscle force generation have been experimentally demonstrated, and mathematical models have been developed to understand these mechanisms. Here, we investigated the minimal set of mechanisms required to describe both the range in peak force from twitch to tetanus and the characteristics of contraction and relaxation. Hereto, we measured calcium fluorescence using Rhod-2 and force kinetics in murine EDL muscles at different stimulation frequencies, ranging from twitch to tetanus. Next, we tested available models in literature with a validated spatiotemporal calcium model as input. Monte Carlo simulations, covering a large parameter space, have been performed to test if the evaluated force models could describe the force dynamics. These simulations showed that calcium activation of the cross bridges sufficed to describe the increment in force from twitch to tetanus. In addition, numerical analysis indicated that extending the models with cooperative activation through strongly attached cross-bridges was required to reproduce the dynamics of contraction and especially of relaxation. Therefore, we hypothesize that the minimal set of mechanisms to describe force dynamics in fast twitch muscle includes both activation by calcium bound to troponin and cooperative activation through strongly attached cross-bridges.