A conventional five-step chemo-mechanical cycle of the
myosin-actin
ATPase reaction, which implies
myosin detachment from actin upon release of hydrolysis products (
ADP and
phosphate, Pi) and binding of a new
ATP molecule, is able to fit the [Pi] dependence of the force and number of
myosin motors during isometric contraction of skeletal muscle. However, this scheme is not able to explain why the isometric
ATPase rate of fast skeletal muscle is decreased by an increase in [Pi] much less than the number of motors. The question can be solved assuming the presence of a branch in the cycle: in isometric contraction, when the force generation process by the
myosin motor is biased at the start of the working
stroke, the motor can detach at an early stage of the
ATPase cycle, with Pi still bound to its catalytic site, and then rapidly release the hydrolysis products and bind another
ATP. In this way, the model predicts that in fast skeletal muscle the energetic cost of isometric contraction increases with [Pi]. The large dissociation constant of the product release in the branched pathway allows the isometric
myosin-actin reaction to fit the equilibrium constant of the
ATPase.