  The power stroke of myosin and the release of inorganic phosphate (Pi) are
pivotal in the conversion of ATP's chemical energy into mechanical work.
Although the precise sequence of these two events remains a subject of debate,
it is generally agreed that Pi-release into the solution doesn't occur
instantly upon the binding of a myosin to actin. Here, we examine how
Pi-release that is not directly coupled with the power stroke affects muscle
contraction. Utilizing a cross-scale mechanics model for a sarcomere unit that
integrates the chemomechanical cycle of individual myosins, we find that
relatively slow Pi-release can markedly improve energy efficiency during muscle
contraction in silico. Our analysis leads us to propose that gradual Pi-release
may offer a route to finely adjust the bond strength of an attached myosin,
thereby indirectly modulating the power stroke to influence muscle performance.
When our model is applied to simulate muscle performance in response to rapid
jumps in Pi concentrations, we observe asymmetric rates of force alteration,
which corroborate previous experimental findings. Indeed, our model's
predictions in the current work are largely consistent with experimental data.
This research provides crucial insights into the kinetics of Pi-release within
the myosin's chemomechanical cycle and its significant regulatory impact on
muscle contraction.
