Muscle Measurements Show Weakly Bound Cross-Bridges Act as a Viscous Drag

Abstract

Molecular measurements of muscle myosin interacting with actin are described by a four-state mechanochemical model. The model contains two bound states, where myosin is attached to actin, and two unbound states, where myosin does not interact with actin. However, previous experiments in solution and on muscle fibers suggest another short-lived interaction between myosin and actin, the weakly bound state. While each of the two bound states can be directly observed at the single molecule level, this third, weakly bound, state is too brief to observe with the typical resolution of these experiments (∼1ms). Does this weakly bound state contribute to muscle force generation and, if so, what is its role? To begin addressing these questions, we compared two models, 1) a four-state model (lacking a weakly bound state) and 2) a five-state model (including a weakly bound state), to published experimental measurements made with whole muscles or muscle fibers. We found that both models fit classical measurements of heat generation as a function of work done by a muscle (the Fenn effect), and measurements of shortening rate as a function of resistive force (the Hill force-velocity relation). However, only the five-state model describes both data sets with a consistent set of parameters. Additionally, both models predict a phenomenon called stretch-activation, defined as a delayed increase in force following rapid lengthening of an otherwise isometric muscle. However, experimental results show the delayed increase in force upon stretch is preceded by an initial peak (phase I) and transient decrease (phase II) in force. Phase II is missing in the four-state model, but present in the five-state model. These results are consistent with the weakly bound state acting as a viscous drag on the thin filament.