Molecular Mechanism of Force Production: From the Difficult 1980s to the Supercharged 1990s and Beyond

Abstract

At the time of the Cold Spring Harbor muscle meeting in 1972 there was much euphoria and great enthusiasm. Essentially all of the investigators there accepted the sliding filament, attached cross-bridge, model of muscle contraction as dogma and many even felt that the problem was solved. Throughout the 1970s and beyond experiments in the muscle field were designed with the underlying assumption of the correctness of the proposed model. After all there was Huxley’s (1969) swinging-tilting cross-bridge model of muscle contraction based on electron microscopic and X-ray diffraction evidence, the transient kinetic mechanical studies of Huxley and Simmons (1971) and the natural way that ATP was proposed to fit into the cross-bridge cycle by Lymn and Taylor (1971). The sliding filament model even appeared in introductory textbooks of physiology. Nonetheless there were difficult but essential issues that had to be addressed. Could the kinetic data derived from the biochemical studies of the actomyosin ATPase reaction mechanism be applied to contracting muscle fibers? Furthermore Huxley (1973) issued a cautionary note at the Cold Spring Harbor meeting when he said that “there is a large gap in our present knowledge, unfortunately right at the heart of the whole problem.” The gap concerned the lack of structural evidence for the proposed changes in the angle of cross-bridge attachment to actin during muscle contraction. This was a enormous problem that would hold up progress in much of the muscle field throughout the 1970s and early 1980s. In fact looking back on this period Huxley (1996) has commented that “…by the mid-1980s, confidence in a straightforward sliding filament mechanism for muscle contraction had been significantly eroded…”. What happened? Why was there skepticism about the sliding filament mechanism of contraction? Between the stagnant 1980s and early twenty-first century there was a spectacular revolution in muscle research that could not have been predicted by even the most ardent dreamer. The investigation of the mechanism of contraction moved from the study of the behavior of billions of cross-bridges in muscle fibers to the investigation of the mechanical properties of individual molecular motors. This work combined with the elucidation of the atomic structures of actin and myosin and the advent of mutagenesis approaches supercharged what would now be called the motility field. But it was still a major challenge to elucidate the mechanism of action of cross-bridges in muscle fibers. In 2004, Hugh Huxley finally proclaimed (Huxley 2004): “…I really do believe that, altogether, there is now incontrovertible evidence for the correctness of the tilting lever-arm model, although of course many important details still remain to be worked out.” (Huxley 2004. With permission John Wiley & Sons Inc) What was the incontrovertible evidence? Was the mechanism of muscle contraction finally solved? These and other issues will be considered in this chapter.