The elementary step that generates force and sinusoidal analysis in striated muscle fibers

The elementary step that generates force by cross-bridges (CBs) in striated muscles is reviewed. A literature search focused on models with validating data to verify a CB scheme; models without substantiating data were briefly mentioned or not included. Experimental data include those carried out under the isometric condition in muscle fibers and single myofibrils, along with results from single molecule and stopped-flow studies. These results suggest that force is generated before phosphate (Pi) is released, and the same force is maintained after Pi is released. These studies assumed that Pi is released from myosin. Some results from isotonic experiments are also reviewed, but the data lack the effect of Pi (or a weak effect). Studies with X-ray crystallography and cryo-electron microscopy suggested that force is generated after Pi release from the active site, and Pi is trapped at the secondary site before it is released to the solution. Thus, the difference in the definition of the "Pi release step" must have caused a controversy. It can be concluded that the results from physiological/single molecule studies and cryo-EM/crystal studies complement each other quite well. With isometric experiments, several perturbations are used to generate force transients: length change, chemical change, pressure release, and temperature increase. A small length change includes sinusoidal waveforms, and a large length change includes 10-20% release/restretch. Chemical perturbation includes [Pi] changes. With temperature studies it was shown that the force generation step is endothermic, indicating heat is absorbed. This is qualitatively explained by a hydrophobic interaction between actin and myosin, and by a cleft closure of myosin.