Mechanokinetic actomyosin model predicts different [orthophosphate]- sensitivity of force and ATP turnover rate during isometric muscle contraction

Alf Mansson^*

• Department of Chemistry and Biomedical Sciences, Linnaeus University, Växjö, Sweden

Release of the ATP hydrolysis product orthophosphate (Pi) from the myosin active site connected with force-generating structural changes are central in actomyosin energy transduction but the temporal order of these events is unclear. A range of data interpreted using simple kinetic schemes (not considering varying cross-bridge strains) suggest that force-generation is intimately associated with the myosin head attachment to actin, preceding Pi-release. Addition of a branched pathway to the kinetic scheme is, however, needed to account for a lower sensitivity to [Pi] of the isometric ATP turnover rate than of force. In contrast, a branched pathway does not seem necessary if data are instead analysed using a mechanokinetic model, taking myosin strain distribution into account. We here corroborated this idea for a model where Pi-release from the active site precedes the force-generating power stroke. We explain the effect based on two components underlying the reduction in isometric force with increased [Pi]. The largest component is due to pre-power-stroke cross-bridges with large elastic strain whereas the smaller component is due to cross-bridges attaching with low elastic strain. Because only the latter myosin heads undergo ATPase cycles, force exhibits greater [Pi]-sensitivity than the ATPase. Changes in model parameter values that minimize the width of the cross-bridge strain distribution do not eliminate the difference in [Pi]-sensitivity of isometric force and ATPase. Such changes, including reduced actin affinity in a pre-power-stroke state, also lead to proportional reduction in isometric force and the number of attached cross-bridges with increased [Pi]. In conclusion, our data suggest that a mechanokinetic model accounts for the combined changes in isometric force, ATPase and number of attached cross-bridges with varied [Pi] in a simpler way than apparently simpler kinetic schemes. A central feature of the results is the explicit demonstration of two components of isometric force with different physiological roles.