Margaria’s Revolution: A Novel Energetic View of Muscular Contraction

Abstract

This chapter is divided into two parts. The first has a historical approach and reports briefly on the evolution of knowledge on muscle, on oxygen as a gas-sustaining life, on energy transformations, and on lactate as an end-product of metabolism during exercise. The ensemble of this knowledge is the basis on which Archibald Vivian Hill and Otto Meyerhof created the first comprehensive theory of the energetics of muscular exercise, centered around lactate as a main energy source for muscle contraction, for which they were awarded the Nobel Prize in Physiology or Medicine in 1922. The subsequent events, most importantly the discovery of high-energy phosphates, which led Rodolfo Margaria to confute Hill and Meyerhof’s theory in 1933, are further summarized. A short biography of Margaria is also provided, with a detailed analysis of the keystone paper by Margaria, Edwards, and Dill, published in 1933, which set the foundation of the School of Milano. In the second part, we provide an analysis of Margaria’s approach to the energetics of muscular exercise, the driving principle of which is compatibility of energetic data with the laws of thermodynamics, which are briefly summarized.

Appendix: Margaria’s Tale of the “Revolution” in Muscle Physiology in the 1930s

2.1.1 Some Historical Notes

It has long been known that the amount of energy that is transformed during muscular exercise is proportional to the rate of oxygen consumption: this indicates that the ultimate energy source is in all cases coming from combustions. The muscle, however, is not a combustion engine, and oxidations are not the chemical reactions providing energy for the production of mechanical work.

It is well-known that a muscle can perform a long series of contractions in absence of oxygen, and that the mechanical characteristics of contraction, as well as heat production, the electrical modifications (action potentials) and so on, are exactly the same in presence as in absence of oxygen: the only difference is due to the fact that in absence of oxygen a muscle is unable to perform prolonged work.

Clearly enough, the fundamental chemical reactions that provide energy to carry out mechanical work are anaerobic. In the years 1920s–1930s, people thought that these reactions consisted of lactic acid formation from glycogen (glycolysis). This theory was promoted especially by A.V. Hill and O. Meyerhof, and it seemed to provide a satisfactory explanation both of the energetic transformations occurring in isolated muscles during contraction, accurately analyzed by the former by measuring heat production, and of the chemical alterations (lactic acid formation, glycogen disappearance, oxygen consumption) occurring in muscle during exercise. More precisely, these authors identified the production of lactic acid from glycogen as the fundamental reaction of muscular contraction: without lactic acid, no muscle contraction would have been possible. Oxidations would have taken place at a second time, to provide energy for glycogen resynthesis and lactic acid removal, since the glycolytic reaction is reversible, in order to sustain a continuous, prolonged muscular activity.

This theory, which was called Hill and Meyerhof’s theory for muscular contraction, was almost universally accepted by the physiologists of those times. A “revolution” in muscular physiology, to use A.V. Hill’s terminology (1932), occurred in 1930, when a young Danish physiologist, E. Lundsgaard, found that a muscle, after poisoning with monoiodoacetic acid, a substance blocking lactic acid formation from glycogen, is still able to carry on multiple contractions, which do not differ at all from the normal ones: only, the total number of contraction is very limited, and at the end the muscle is in a typical contraction state. In these conditions, the muscle, instead of becoming acid, as usual, becomes alkaline. The energy for work production by the muscle seemed to come from the splitting of a substance just discovered in muscles, creatine phosphate, into its two components (creatine and phosphate), a strongly exergonic reaction indeed.

Hill and Meyerhof’s theory had to be modified to account for this new discovery. Creatine phosphate splitting was then considered as the reaction that was directly involved in energy supply for mechanical work production, and this reaction was supposed to be located upstream of the reactions of glycolysis.

This last was moved from the first to the second row, but quantitatively speaking maintained its full meaning, as far as the chemical and energetic processes that occur during muscular contraction are concerned. In particular, lactic acid formation from glycogen was still considered an obligatory and necessary step in the chain of reactions involved in muscular contraction; and lactic acid was still considered and obligatory intermediate product of glycogen oxidative metabolism. So, glycolysis was still considered the main, although indirect, anaerobic energy source for muscular contraction.

Lactic acid formation from glycogen still remained the only mechanism for the oxygen debt contraction, in agreement with the original scheme prospected by A.V. Hill, and glycogen resynthesis from lactic acid was still the mechanism for the payment of the same oxygen debt.

According to this hypothesis, we should have found a proportionality between the quantity of lactic acid formed as a consequence of exercise and the amount of the oxygen debt; and the disappearance of lactic acid from blood should have gone on in parallel to the process of oxygen debt payment.

Experiments carried out (1933) on man by R. Margaria, R.H.T. Edwards, and D.B. Dill did not confirm this hypothesis. First of all, they found that lactic acid does not increase in blood at all as a consequence of light or moderate exercise, although also in these cases there is a contraction of a remarkable oxygen debt: an increase of lactic acid in blood occurred only after strenuous muscular exercise, the intensity of which was close to or higher than the maximum oxygen consumption.

In these conditions, the increase of the oxygen debt appeared to proceed at the same rate as, and linearly to, the increase of lactic acid in blood.

On the other side, the kinetics of lactic acid disappearance from blood was definitely different from the kinetics of oxygen debt payment. Lactic acid removal from blood during recovery appeared as a simple exponential process with a half-time of 15 minutes, whereas the time course of oxygen consumption during recovery looked like a more complex process, in which at least two exponential functions were involved: the first being very fast, with a half-time of 0.5 min, and the second very slow, with a half-time of 15 min, id est of the same order of lactic acid removal from blood.

It is evident from this data that lactic acid metabolism is so slow, that it cannot account for the fast and intense oxidative processes that take place in the organism during intense muscular work: clearly enough, glycogen and other substrates, which are burned in the muscle during exercise, cannot take the lactic acid path, because the metabolism of this substance would slow down the entire chain of oxidative reactions to a much slower rate than that actually observed and deducible from oxygen consumption.

In conclusion, the splitting of glycogen to lactic acid did not seem to be a process compatible with the chemical and energetic events that occur during normal muscular exercise, except as an emergency mechanism during strenuous exercise.

In these last conditions, lactic acid formation actually has the meaning of the contraction of an oxygen debt, as suggested by Hill.

Notwithstanding, the oxygen debt contracted during moderate-intensity exercise cannot be due to glycolysis, but to other anaerobic reactions, which Margaria, Edwards, and Dill thought to identify with creatine phosphate splitting. For this reason, they made a distinction between the fraction of the oxygen debt due to creatine phosphate splitting, which for this reason was called alactacid, and is paid very quickly during the recovery period, and the other fraction due to glycolysis (lactacid oxygen debt), which is paid much more slowly, in parallel to lactic acid disappearance from blood.

The quantity of these two fractions of the oxygen debt was plotted as a function of the intensity of exercise (or of the oxygen consumption) in the diagram reported in Fig. 3 (actually Fig. 2.8 in this appendix).

Fig. 2.8

Total alactacid and lactacid debt as a function of oxygen consumption. The type of exercise consisted in running on a treadmill at the speed and incline indicated on the abscissa. The exercise lasted 10 min, except when differently indicated (on the right) at the maximal exercise intensities. From Margaria et al. 1933. This Figure is Fig. 3 of Margaria’s book

From these experiments it was clear that the combustion coefficient of lactic acid, id est the fraction of lactic acid that is burned, as compared to the total amount of lactic acid that disappears, is not ¼, as observed by Meyerhof on isolated muscle, but sensibly less. The oxygen consumption that is necessary to remove a given quantity of lactic acid from blood in 1 min can be calculated for any given pre-assigned value of the combustion coefficient: if we give to this coefficient a value of ¼, the oxygen consumption involved in the process appeared to be higher than the actually observed one. With this approach, it was remarked that the combustion coefficient of lactic acid could not possibly be higher than about 1/8–1/10.

A few years later, it was found that creatine phosphate splitting can occur only in presence of adenosine-tri-phosphate (ATP), a compound that K. Lohmann isolated in muscle in 1928, and that can be split in adenosine-di-phosphate and inorganic phosphate: this reaction is strongly exergonic too. This substance, or others of the same type, is nowadays considered as the fundamental exergonic reaction, not only in muscular contraction but in all vital processes requiring the production of different forms of energy.

For this reason, this reaction has been inserted upstream of creatine phosphate splitting in the chain of reactions that occur during muscular contraction.

By so doing, the role of creatine phosphate has progressively evolved to get the meaning of a provider of phosphate and energy for the resynthesis of adenosine-tri-phosphate from adenosine-di-phosphate.

From: Rodolfo Margaria (1975). Fisiologia muscolare e meccanica del movimento. Biblioteca della EST, Mondadori, Milano, pp. 10–16. Translation from Italian by Guido Ferretti. Figures omitted, except Fig. 3.