Muscle cross-bridge chemistry and force.

The recent article by Baker et al. (1999) presents a thermo-dynamic formalism that challenges the commonly held assumption that force production by muscle is localized to individual actin-bound myosin molecules. By assuming that the chemical reaction for the force-producing step is close enough to equilibrium to set ⌬G ϭ 0, the sum of the chemical and mechanical potentials of the products can be set equal to the sum of the chemical potentials of the reactants. To obtain the chemical potentials, Baker et al. chose the reaction in which A is actin, M is a myosin cross-bridge, D is MgADP, and P i is orthophosphate. Force is produced as M.D.P i binds A and dissociates P i. The nature of the mechanical potential, ␮ mech , is not constrained in their formalism. The standard free energy equation for the near-equilibrium force-generating step is In contrast, the mechanical potential is constrained in almost all previous molecular level models. The authors note that those models include the assumption that the internal work performed by myosin conformational changes when actin binds is localized to displacements of elastic elements associated with individual myosin cross-bridges (Huxley, 1957; Hill, 1974). Some critical properties of force production are determined experimentally by measuring cross-bridge orientation and force as a function of [P i ], during isometric contraction of small bundles of skinned skeletal muscle fibers. Force is found to decrease with increasing [P i ], but the distribution of cross-bridge orientations remains constant, within 1% (Baker et al., 1999). The lack of correspondence between force, cross-bridge orientation, and the chemical equilibrium in Eq. 1 leads the authors to propose that those twentieth century models of contraction, which have force production localized to chemical reactions associated with individual cross-bridges, should be abandoned. They suggest that force production is distributed among, not within, the myosin cross-bridges, and they describe several muscle fiber properties in light of that hypothesis. Measurements of force generated in vitro by isolated individual cross-bridges bound to actin (Warrick et al., 1993), which certainly suggest that localized force production is possible, are not addressed. The thermodynamic formalism and the experiments reported by Baker and colleagues are thought-provoking. The authors identify several existing limitations to a full understanding of force production by skeletal muscle fibers. However, there are two elements contributing to their proposal that force generation is not localized to chemical reactions at individual cross-bridges that are problematic, …