A classical lay summary by Axel Fenwick, Ph.D., Johns Hopkins University

Our muscle cells are packed with straight, parallel filaments that slide past each other during contraction, shortening the cell and ultimately the entire muscle. Some of the filaments are made of myosin and have “heads” that protrude out to form cross-bridges with neighboring filaments made of actin. When myosin heads bind to actin they use chemical energy from the breakdown of ATP to generate a pulling force against actin filaments, then detach and prepare to bind again. This repetitive process of binding, applying force, and unbinding is known as the cross-bridge cycle. This cycle is the fundamental source of force production in our muscles, and as such, various models characterizing it have been developed and modified over the last 60 years, growing in nuance and complexity along with our understanding of muscle biomechanics.

Andrew Huxley first characterized this cycle in 1957 with a simple two-state model consisting of an unbound myosin state and a bound myosin-actin state (Huxley 1957). Assigning experimentally determined values to this model allowed Huxley and others to better predict the dynamics of muscle force generation and energy usage. Huxley’s model assumed that myosin heads break down a single ATP molecule over the course of a cross-bridge cycle, but did not define particular steps to do so. A crucial addition to this model was made in 1971 by Richard Lymn and Edwin Taylor who subdivided the bound myosin-actin state into two distinct states: weakly bound and strongly bound (Lymn and Taylor 1971; See associated figure). The weakly bound step describes a state in which the myosin head has broken ATP (adenosine triphosphate) into ADP (adenosine diphosphate) and phosphate (Pi), the head has just attached to actin, but has not yet released ADP or Pi. In this state, the myosin is only partially bound to actin and little or no force is produced. The myosin head then rotates into a strongly bound configuration, which allows ADP and Pi to be released. In this state, myosin performs the primary force-producing “power stroke” of the cross-bridge cycle as it pulls on the actin filament.

Only a few years after Lymn and Taylor presented this model, it was discovered that the release of ADP and Pi from the myosin head were not simultaneous. Pi release from myosin precedes the release of ADP, and force is generated while ADP is still bound to myosin, resulting in a state that was absent in Lymn and Taylor’s model (White and Taylor 1976). Evidence also suggested that the release of Pi corresponded with the start of the myosin power stroke. However, whether the release of Pi initializes the power stroke or if instead the initial motion of the power stroke liberates Pi remains controversial to this day. The power stroke continues for a brief period after ADP is released, but new ATP rapidly binds to myosin, evoking a conformational change in the head which detaches it from actin. Unbound to actin and with fresh ATP, myosin is then primed to start another cycle. More recent cross-bridge models capture additional steps, and some go further to include cooperative dynamics or merge with models of actin-filament activation. However, these models are all predicated on the earlier models and assumptions posited by Huxley, Lymn, and Taylor. Their work set the foundation on which we continue to build our understanding of the mechanisms of muscle contraction.

 

REFERENCES

 

Huxley AF (1957) Muscle structure and theories of contraction. Prog Biophys Biophys Chem 7:255–318

Lymn RW, Taylor EW (1971) Mechanism of adenosine triphosphate hydrolysis by actomyosin. Biochemistry 10:4617–4624. https://doi.org/10.1021/bi00801a004

White HD, Taylor EW (1976) Energetics and mechanism of actomyosin adenosine triphosphatase. Biochemistry 15:5818–26