The Role of Adenosine Triphosphate in Muscular Contraction

THE ROLE OF ADENOSINE TRIPHOSPHATE IN MUSCULAR CONTRACTION JACOB SACKS* I. Development ofOpposing Interpretations Adenosine triphosphate, ATP, was firstdiscovered in muscle and is present in that tissue in considerably higher concentration than in any other part of the mammalian organism. There is overwhelming evidence that this substance plays an essential part in the contraction process, but despite the enormous amount ofinvestigation bearing on the point, its exact function is still obscure. Studies on the enzyme systems ofmuscle and on the isolated contractile proteins have given a reasonably consistent picture. However, observations ofthe chemical changes taking place during muscular contraction lead to interpretations at variance with those derived from in vitro studies. The sine qua non ofthe formulation derived from in vitro studies is that the dephosphorylation of ATP to ADP and orthophosphate (Pi) is the immediate source ofthe energy for contraction. Although a few investigators have reported that this reaction takes place in the muscle, the burden offindings from a variety of direct and indirect approaches is that there is no convincing evidence that such a dephosphorylation does take place in the course ofa single twitch or a short tetanic contraction [1-5]. Writers ofreview articles have made diametrically opposite interpretations of the experimental findings. For example, Mommaerts et al. [6] state: "Yet, scientific rigor requires a direct demonstration ofa breakdown ofATP as a reactionimmediately connectedwithcontractionorrelaxation, and, this not having been made, the theory is in a most peculiar position." On the other hand, Perry [7] explains the failure ofChance and Connel- * Department of Chemistry, University ofArkansas, Fayetteville, Arkansas. Part ofthe experimental work referred to was supported by grants from the National Institute ofArthritis and Metabolic Diseases, National Institutes ofHealth. 285 Iy [5] to find any significant increase in ADP content during a single twitch ofisolated frog muscle by stating that the actual changes in ADP concentration were very much greater than those actually measured by the spectrophotometric method used, because ofthe occurrence ofappreciable rephosphorylation by phosphokinases, e.g., creatine kinase. The function ofmusclerequires thatthe rate ofenergy output be capable ofenormous increases within a fraction ofa second. To supply the energy for contraction, it is therefore necessary that there be some source independent ofblood flow and oxygen supply. Because a large part ofthe early investigation was carried out on isolated frog muscle, which has a much greater capacity for survival and function in the absence of oxygen than does mammalian muscle, the development has been in terms ofnon-oxidative reactions. The conversion ofglycogen to lactic acid, the hydrolysis of phosphocreatine (PC), and the dephosphorylation of ATP have successively been identified as the source ofenergy for contraction. The most firm basis for the generally held view—that the dephosphorylation ofATP is the immediate source of the energy for contraction—derives from the finding that myosinhas the properties ofan active ATPase and the demonstration that glycerinated muscle fibers or threads of actomyosin can be made to shorten in the presence of Mg ion upon the addition of ATP. However, the ATPase ofmyosin requires Ca ion for activation and is inhibited by Mg ion. It is now recognized that the complex actomyosin, rather than myosin itself, undergoes this shortening in the isolated system. The ATPase action of actomyosin does require Mg for activation, but seems also to require the presence ofsome free Ca ion [8]. The presence in muscle ofan enzyme which can transfer a phosphate group from PC to ADP, to form ATP, or from ATP to creatine, plus the established finding that a muscle contracting under conditions ofreduced oxygen supply for a series oftwitches, or for a tetanus ofa few seconds ' duration, undergoes a decrease in PC content has been coupled with the shortening offibers induced by ATP in the current formulation. This can be stated in the following terms: the immediate energy for contraction is furnished by the dephosphorylation ofATP to ADP and Pi; the initial reaction in recovery is resynthesis ofthe ATP by transfer ofthe phosphate group ofPC. Muscle also contains a relaxing factor [9, 10] which is isolated from homogenates after removal of the myofibrils. This relaxing factor is a 286 Jacob Sacks · Adenosine Triphosphate in Muscular Contraction Perspectives in Biology and Medicine · Spring 1964 granular material, presumably...