VOL. 4 (1950) PRIMARY REACTION IN MUSCULAR ACTIVITY 55 



It is still difficult to judge the exact physiological meaning of the described reaction, 

 but it is of obvious interest to see whether a theory ascribing to it the significance of the 

 primary event in muscular activity would meet the standards set by Hill's thermal 

 measurements. As is well known, a single anaerobic twitch, in which the primary event 

 would take place only once, is accompanied by an appearance of about 3-10"^ calories 

 per gram muscle^*. In the given picture, this primary event would involve the combi- 

 nation of 3-10"' or more moles of ATP with the structure protein. Thus the heat effect 

 of this combination per mole ATP would have to be 10 000 calories or less. This has not 

 yet been measured, but the requirement seems to be quite in line with what could be 

 expected. It seems a permissible hypothesis therefore to identify the primary event of 

 contraction with a combination and further reaction between ATP and (acto-) myosin. 



We shall now turn to a discussion of the chemical basis of relaxation, and will have 

 to correlate this event, by exclusion, with the enzymatic breakdown of ATP or its 

 myosincomplex. In connection with the close association between ATPase and myosin, 

 the current assumption is that it is the myosin- ATPase itself which hydrolyses the ATP, 

 and thus makes the energy of this reaction available to the contractile structure. After 

 an extensive study of the activity of myosin-ATPase it has been estimated^^ that in 

 muscle the overall speed of hydrolysis by this enzyme can amount to only about 3 • io~3 

 mg P per mg myosin per minute. The actual speed of ATP breakdown in active mam- 

 malian muscle is much higher. From Lundsgaard's^^ results with frog muscles the 

 writer estimated the speed of this process to be around 2- io~^ mg P per mg myosin per 

 minute, and a reinvestigation of all relevant data ("Chapter III) gave rise to the same 

 or even higher values. Likewise, Braverman and Morgulis^ essentially confirmed 

 these results and reported the same disproportion. To reformulate the difficulty: the 

 actual speed of breakdown of ATP in active muscle proceeds a hundred times faster than 

 the myosin-ATPase under the given circumstances can account for. Several explanations 

 of this discrepancy seem possible. Either, intact muscle contains unknown potent 

 activators of the myosin-ATPase. Or, the true reaction is not at all a hydrolysis of ATP, 

 but a phosphorus transfer to some acceptor ; in fact there are indications (Lundsgaard^^ ; 

 Cori and Cori'') that a P-transfer of ATP to fructose-6-phosphate under formation of 

 hexose-diphosphate is a significant reaction. Further, it is not yet possible to judge 

 which role the new ATPase described by Kielley and Meyerhof^^ has. Several 

 possibilities for a solution of the dilemma thus seem to exist, and the identification of 

 the exact course of ATP breakdown may throw a significant light upon the question of 

 relaxation. At this moment however, no suggestions seem to be indicated. 



The above considerations have been developed on the basis of in vitro experiments 

 only, and the task remains of identifying the sequence of events in the contraction cycle 

 of a living muscle. In this field, we owe most direct and illuminating experiments to 

 Dubuisson^' ^, who studied the rapid pn changes which accompany a contraction. It 

 was found that first an acidification occurs which in favourable specimens was preceded 

 by a small reaction change in the opposite direction. Then there is an alkalinization, 

 followed in turn again by an acidification. The last two changes could be identified 

 convincingly: they are due to the dephosphorylation of phosphocreatine, and to the 

 formation of lactic acid. The latter process takes place only after the mechanical events, 

 the former is coincident with the relaxation. The initial acidification is correlated with 

 the initiation of the contraction process, and is therefore of great interest. Dubuisson 

 assumes it to be due to hydrolysis of ATP, but this conclusion is tentative ; acidification 

 References p. sOJsy. 



