Mechanism of force generation by myosin heads in skeletal muscle

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Abstract
Muscles generate force and shortening in a cyclical interaction between the myosin head domains projecting from the myosin filaments and the adjacent actin filaments. Although many features of the dynamic performance of muscle are determined by the rates of attachment and detachment of myosin and actin1, the primary event in force generation is thought to be a conformational change or ‘working stroke’ in the actin-bound myosin head2,3,4,5,6,7,8. According to this hypothesis, the working stroke is much faster than attachment or detachment, but can be observed directly in the rapid force transients that follow step displacement of the filaments3. Although many studies of the mechanism of muscle contraction9,10,11,12,13 have been based on this hypothesis, the alternative view—that the fast force transients are caused by fast components of attachment and detachment14,15,16,17 —has not been excluded definitively. Here we show that measurements of the axial motions of the myosin heads at ångström resolution by a new X-ray interference technique18 rule out the rapid attachment/detachment hypothesis, and provide compelling support for the working stroke model of force generation.