PHYSIOLOGY OF CARDIAC MUSCLE 



active site on the actin filament, to o, the equilibrium 

 position of the sliding element on the myosin filament, 

 is denoted by X. During steady shortening, X de- 

 creases at a constant rate. Initially, the groups M and 

 A are detached; in response to the action potential 

 which invades the Z membrane and the actin fila- 

 ments, combination of A and M takes place spon- 

 taneously with the equilibrium in favor of the com- 

 bined state. Since many A and U sites exist, any 

 number of positions of the two filaments with regard 

 to each other can be attained. In an average con- 

 traction many A-M linkages will be formed and 

 broken. If the initial reaction is spontaneous and 

 exergonic, the recovery reaction, i.e., breaking an 

 A-M bond, will require the input of energy from an 

 available source such as ATP. The sites on each 



o 



protein are calculated to be about loo A apart, so 

 as the muscle shortens more sites come into apposi- 

 tion. 



This model also satisfies the thermodynamic data 

 of Hill (lOo) obtained on striated muscle which led 

 to his classical formulations, viz.: /) the hyperbolic 

 force-velocity relationship, 2) the proportionality 

 between rate of heat liberation and the speed of 

 shortening, and j) the proportionality between the 

 rate of total energy liberation and the decrement 

 below isometric tension (106, 194). 



The biochemical events which may be postulated 

 to drive the sliding model are as follows: 



actin -|- myosin — ► actomyosin 



(22) 



The myosin is thus regarded as "energy rich" and 

 capable of "pulling" the actin filament toward it 

 by combining with it in the highly oriented manner 

 imposed by the ultrastructure of the myofibril. The 

 actomyosin bond thus formed is broken (either in 

 more vigorous shortening or by relaxation) by re- 

 action of the actomyosin with ATP as follows : 



actomyosin -f- ATP — ► myosin-ATP -|- actin 



(23) 



The myosin-ATP complex, which may be regarded 

 as an enzyme-substrate complex, is then split by 

 the ATPase activity of myosin as follows: 



myosin - ATP + H2O ^ myosin -1- P, -|- ADP (24) 



Levy & Koshland (135) have studied reaction 24 

 with HoO^' and have produced evidence that phos- 

 phomyosin is formed transiently in this reaction. A 

 significant and paradoxical difference between the 

 ATPase activity of myosin and the ATPase activity 

 of the myofibril is that extracted purified myosin 

 ATPase is strongly inhibited by Mg++ (and activated 



by Ca+^), whereas both Ca++ and Mg++ activate 

 the myofibrillar ATPase (191). The ADP formed 

 in equation 24 is then rephosphorylated through 

 electron transport. Although Huxley (106) prefers 

 to write equation 23 with actin-ATP as the complex 

 formed, the lack of ATPase activity in actin makes 

 myosin a more likely candidate. The question of the 

 direction of movement of the filaments must depend 

 upon the state of activation of the Z membrane which 

 distributes the action potential of the membrane to 

 the contractile elements (108). It is also of interest 

 that this model obviates the necessity of designating 

 the time in the contractile cycle when ATP splitting 

 occurs; it occurs during all movements of the fila- 

 ments in order to permit the making and breaking 

 of the points of attachment between actin and myosin. 



The sliding model thus provides a new and stimu- 

 lating hypothesis for contemplation. It is certainly 

 not established but, at the moment, has so many at- 

 tractive features that it will be studied intensively in 

 the future. The other models which have been pro- 

 posed have strengths and weaknesses which deserve 

 mention. Szent-Gyorgyi (233) visualizes a folding 

 model in which actin and myosin combine in the 

 presence of ATP and shorten, much as actomyosin 

 gels or glycerinated fibers do in vitro. It is unlikely, 

 however, from the electron microscopic studies that 

 actin and myosin combine in the myofibril as they do 

 in vitro. More recently Szent-Gyorgyi (235) has 

 suggested that muscular contraction may be a sub- 

 molecular phenomenon, involving protomyosins (frag- 

 ments of myosin) and the triplet state of their elec- 

 trons. The triplet state occurs when an electron is 

 raised to an excited state by the absorption of energy 

 which reverses its spin. The excited electron is trapped 

 because it cannot drop back to the original energy 

 level of its partner which is spinning in the same direc- 

 tion and as a result the lifetime of the excited state 

 is lengthened about a millionfold. The molecule which 

 contains the uncoupled electrons is in an unbalanced 

 and more reactive state, like a free radical and in 

 Szent-Gyorgyi's view, molecular contraction would 

 be a quantum mechanical process involving displace- 

 ment of myosin fragments (235). 



Morales & Botts (165) have suggested that the 

 primary event in muscular contraction is a folding 

 of a Mg-myosin complex to which ATP is adsorbed 

 (acting as a polyelectrolyte) in an electrostatic en- 

 vironment altered by the passage of the action po- 

 tential. The hydrolysis of ATP is visualized as oc- 

 curring at the end of contraction to permit the 

 rebuilding of the appropriate polyelectrolyte structure 



