Chemomechanical energy regulates time-dependent changes in thin filament activation.

Abstract

Muscle activation is a reaction that turns on and off as a binary switch, which sharpens the contrast between two proposals for the energy of activation, namely, allosteric or chemomechanical. Binary switching rules out sequential allosteric models. That a segment rather than the entirety of the thin filament switches on and off rules out the concerted allosteric model. By contrast, switching data fit a model in which mechanical energy is combined in the Gibbs-Duhem equation for binary change in probability of M-state. To be consistent with a binary system, the probability of M-state is the extensive conjugate of mechanical energy in modified Gibbs-Duhem (mGD). Time dependent changes of mGD accurately predict that a source of mechanical impulses, such as driven by myosin, shifts the probability of a switch to longer times. From time dependent mGD, we derived a set of probable outcomes (mGD sample space), that can be tested by observing switching behavior of individual segments. Sample space mGD predicts that a segment in M-state moves a single unloaded thin filament at the unregulated actomyosin rate for the time the switch is on. Because load acts specifically on mechanical energy, a load can change the probability of M-state in sample space mGD by a mechanism consistent with the extensive variable, such as forced addition of subunits to a segment in M-state. Continuous sum produces a sample space for the time dependent response of ensemble units. Overlap of myosin S-1 in the sarcomere determines the size of the ensemble. Although sample space mGD does not vary by the number of subunits, changes in ensemble size change the amplitude of the response. Normalizing amplitude to overlap by careful experimentation is required for comparison with sample space mGD.