|Ph.D Student||Yedid Moran|
|Subject||Theories of Muscle Contraction: The Dependence of Cross-|
Bridge Kinetic Rates on the Filament Sliding
|Department||Department of Biomedical Engineering||Supervisor||Professor Amir Landesberg|
|Full Thesis text|
Explanations for the basic skeletal and cardiac muscle characteristics, such as the force-velocity relation, the Fenn effect and the high contractile efficiency, are still controversial. These properties are dominated by the actomyosin cross-bridge (XB) dynamics. Numerous models have been suggested to describe XB dynamics and its dependence on the mechanical loading conditions. These studies suggest that XB dynamics depends on displacement, load or velocity. Theories of displacement-dependent XB kinetics stem from Huxley's classic theory of muscle contraction. Load-dependent motor kinetics is based on recent single molecule studies. However, there is a gap between our knowledge at the single-molecule level and the sarcomere level on both XB-dynamics and energetics aspects. We suggest, in the framework of the functional sarcomere, that XB kinetic rates are simple functions of filament sliding velocity (V). The velocity-dependent kinetics provides analytical expressions for the Hill's force-velocity relationship, and the observed relationships between energy consumption and generated work.
The study scrutinizes the three putative theories by testing the effects of shortening and lengthening on the generated force and stiffness. Trabeculae were isolated from rat right ventricles. Sarcomere length was measured by laser diffraction. Changes in the number of strong XBs (NXB) were evaluated by measuring the dynamic stiffness. Ramp stretches and releases at different velocities and onset times were imposed over isometric sarcomere contractions.
Stretches yielded parallel increases in force and stiffness at all stretch velocities. This observation is incongruent with a displacement dependent kinetics. The force per XB during stretch was constant, independent of the velocity, and equal to the isometric force per XB, with a load dependent kinetics.
The stiffness difference between ramp perturbations and isometric regime, normalized by the instantaneous isometric stiffness, (DK) was a linear function of velocity and ramp duration; Moreover, DK was independent of ramp onset time. DK development rate depended linearly on the lengthening velocity, with a slope of 6.73?0.98?m-1. During shortening, the DK decline rate depended linearly on the shortening velocity, with an identical slope of -6.70?1.43?m-1. The symmetrical dependence of DK change rate on the V, for both stretches and releases, is explained only by the velocity-dependent hypothesis, a mechanism that also explains the muscle high contractile efficiency.
The obtained body of evidence strongly supports the hypothesis that XB weakening rate is a linear function of V.