Crossbridge cycle

The crossbridge cycle in muscle. Myosin crossbridges interact cyclically with binding sites on actin filaments. Note that the energy release step—when ATP is broken down to ADP—recocks the crossbridge head. 

Just as important as the maximum active force a muscle can exert at various lengths, is the rate at which the muscle shortens as a function of the force load, i.e., the force-velocity curve. Both the length-tension curve and the force-velocity curve vary according to the degree of activation of a muscle. The rate at which crossbridges cycle is an inverse function of the load force (Figure 4). 

In skeletal muscle, calcium binds to troponin and causes the repositioning of tropomyosin. As a result, the myosin-binding sites on the actin become uncovered and crossbridge cycling takes place. Although an increase in cytosolic calcium is also needed in smooth muscle, its role in the mechanism of contraction is very different. Three major steps are involved in smooth muscle contraction ... 

Upon entering the smooth muscle cell, Ca++ ions bind with calmodulin, an intracellular protein with a chemical structure similar to that of troponin. The resulting Ca++-calmodulin complex binds to and activates myosin kinase. This activated enzyme then phosphorylates myosin. Crossbridge cycling in smooth muscle may take place only when myosin has been phosphorylated. 

The dephosphorylation of myosin requires the activity of myosin phosphatase. Located in cytoplasm of the smooth muscle cell, this enzyme splits the phosphate group from the myosin. Dephosphorylated myosin is inactive crossbridge cycling no longer takes place and the muscle relaxes. 

In smooth muscle, myosin crossbridges have less myosin ATPase activity than those of skeletal muscle. As a result, the splitting of ATP that provides energy to "prime" the crossbridges, preparing them to interact with actin, is markedly reduced. Consequently, the rates of crossbridge cycling and tension development are slower. Furthermore, a slower rate of calcium removal causes the muscle to relax more slowly. 

All of these factors (ANS stimulation, blood-borne and locally produced substances) alter smooth muscle contractile activity by altering the intracellular concentration of calcium. An increase in cytosolic calcium leads to an increase in crossbridge cycling and therefore an increase in tension... 

Changes in heart rate also affect the contractility of the heart. As heart rate increases, so does ventricular contractility. The mechanism of this effect involves the gradual increase of intracellular calcium. When the electrical impulse stimulates the myocardial cell, permeability to calcium is increased and calcium enters the cell, allowing it to contract. Between beats, the calcium is removed from the intracellular fluid and the muscle relaxes. When heart rate is increased, periods of calcium influx occur more frequently and time for calcium removal is reduced. The net effect is an increase in intracellular calcium, an increased number of crossbridges cycling, and an increase in tension development. 

These messengers also play a role in regulating contraction of myometrium, which consists of smooth muscle fibres. Contraction is controlled by increases in the concentration of cytosolic Ca ions. Prostaglandins activate Ca ion channels in the plasma membrane of the fibres oxytocin activates release of Ca from intracellular stores. The increase in concentration of Ca ions leads to activation of myosin light-chain kinase which leads to crossbridge cycling and contraction (as described in Chapter 22 Figure 22.12). 

Kentish, J.C., McCloskey, D.T., Layland, J., et al. 2001, Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ Res, 88(10), pp 1059-65. 

Fig. 7. (A) The crossbridge cycle showing the way the myosin head attaches and...

Much is known about the steps in the biochemical reaction of ATP breakdown by myosin and how these relate to the production of force by the crossbridge. However, since it is no longer attached to the myosin thick filament, myosin SI cannot be an adequate model for a strained crossbridge. Thus data from muscle fibers (e.g., the dependence of phosphate affinity on strain) must also be considered. In this review we attempt to summarize the currently known structural data on myosin and produce a synthesis of this with the biochemical data. We start with an analysis of the polymorphism of the myosin crossbridge and relate this to the crossbridge cycle proposed by Lymn and Taylor (1971). 

Zeng, W., Conibear, P. B, Dickens, J., Cowie, R., Wakelin, S., Malnasi-Csizmadia, A., and Bagshaw, C. (2004). Dynamics of actomyosin interac mmtions in relation to the crossbridge cycle. Phil. Trans. R Soc. B 359, 1843-1855. 

The basic assembly of striated muscles has been described in detail in Squire et al. (2005), Granzier and Labeit (2005), and Brown and Cohen (2005) and ideas about the crossbridge cycle were described in Geeves and Holmes (2005). Many of the ideas about the crossbridge mechanism have come from X-ray diffraction studies of muscle, but to many people such studies are difficult to understand and, even to some practitioners of the technique, it is easy to be misled by certain types of results. The technique itself is immensely powerful and may be one of the very few approaches that can actually probe molecular structural changes that occur in intact muscles while they are undergoing their usual function, namely, tension... 

---