Activation of striated muscle: Nearest-neighbor regulatory-unit and cross-bridge influence on myofilament kinetics

We have formulated a three-compartment model of muscle activation that includes both strong cross-bridge (XB) and Ca²⁺-activated regulatory-unit (RU) mediated nearest-neighbor cooperative influences. The model is based on the tight coupling premise - that XB retain activating Ca²⁺ on the thin filament. Using global non-linear least-squares, the model produced excellent fits to experimental steady-state force-pCa and ATPase-pCa data from skinned rat soleus fibers. In terms of the model, nearest-neighbor influences over the range of Ca²⁺ required for activation cause the Ca²⁺ dissociation rate from regulatory-units (k_off) to decrease and the cross-bridge association rate (f) to increase each more than tenfold. Moreover, the rate variations occur in separate Ca²⁺ regimes. The energy of activation governing f is strongly influenced by both neighboring RU and XB. In contrast, the energy of activation governing k_off is less affected by neighboring XB than by neighboring RU. Nearest-neighbor cooperative influences provide both an overall sensitization to Ca²⁺ and the well-known steep response of force to free Ca²⁺. The apparent sensitivity for Ca²⁺-activation of force and ATPase is a function of cross-bridge kinetic rates. The model and derived parameter set produce simulated behavior in qualitative agreement with steady-state experiments reported in the literature for partial TnC replacement, increased [P_i], increased [ADP], and MalNEt-S1 addition. The model is an initial attempt to construct a general theory of striated muscle activation - one that can be consistently used to interpret data from various types of muscle manipulation experiments.