CHAPTER IV
SOURCE OF THE ENERGY OF MUSCLE WORK, WITH SOME THEORIES OF PROTEID METABOLISM
Topics: Relation of muscle work to energy exchange. Views of Liebig. Experimental evidence. Relation of nitrogen excretion to muscle work. Significance of the respiratory quotient in determining nature of the material oxidized. Fats and carbohydrates as source of energy by muscles. Utilization of proteid as a source of energy. Formation of carbohydrate from proteid. Significance of proteid metabolism. Theories of Carl Voit. Morphotic proteid. Circulating proteid. General conception of proteid metabolism on the basis of Voit’s theories. Pflüger’s views of proteid metabolism. Rapidity of elimination of food nitrogen. Methods by which nitrogen is split off from proteid. Theories of Folin. Significance of creatinin and of the percentage distribution of excreted nitrogen. Endogenous or tissue metabolism. Exogenous or intermediate metabolism. Needs of the body for proteid food possibly satisfied by quantity sufficient to meet the demands of tissue or endogenous metabolism. Bearings of Folin’s views on current theories and general facts of proteid metabolism. Large proteid reserve and voluminous exogenous metabolism probably not needed. Importance of feeding experiments in determining the true value of different views.
As we have already seen, every form of muscular activity begets an increase in the energy exchange of the body. Between the two extremes of absolute rest and excessive muscular exertion, we find differences of 2000 calories or more per day as representing the degree of chemical decomposition corresponding to the particular state of muscular activity. The work of the involuntary muscles, such as have to do with peristalsis, respiration, rhythmical beat of the heart, etc., is a relatively constant factor, though naturally subject to some variation, as has been pointed out in other connections. External muscular activity, however, is the one factor above all others that modifies the rate of energy exchange. A little longer walk, a heavier load to carry, a steeper hill to climb, any increase great or small in the activity of the muscles of the body, means a corresponding increase in chemical decomposition, with increased output of the ordinary products of tissue oxidation. The material so consumed, or oxidized, must be made good to hold the body in equilibrium; the supplies drawn upon are to be replaced, if the tissues of the body are to be kept in a proper state of efficiency.
What is the nature of the material used up in connection with muscle work? As can readily be seen, this is an important question, for on its answer depends, in some measure at least, the character of the proper intake, or food, to be supplied in order to make good the loss. If the energy of mechanical work, the energy of muscle contraction, comes from the breaking down of proteid matter alone, then obviously excessive muscular work would need to be accompanied, or followed, by a generous supply of proteid food. If, on the other hand, external work means liberation of energy solely from non-nitrogenous materials, then it is equally clear that fats and carbohydrates are the proper foods to offset the drain incidental to vigorous muscular action.
The views of Liebig, briefly referred to in a previous chapter, held sway over physiologists for many years. His dictum that proteid foods were true plastic foods, entering into the structure of the tissues of the body, and that they alone were the real sources of muscular energy, met for a time with no opposition. It was not until the advent of a more critical spirit, accompanied by a fuller appreciation of the necessity of experimental evidence, that physiologists began to test with scientific accuracy the validity of the current views. It is worthy of note that long prior to this time, even before oxygen was discovered, the far-sighted and resourceful John Mayow, in his work with the various “spirits” of the body and their relation to respiration, etc., evolved the view that muscular power has its origin in the combustion of fat brought to the muscles by the blood and burned there by aid of a gas or “spirit” taken from the air by the lungs, and likewise carried to the muscles by the circulating blood. Considering the time when Mayow lived and the dearth of true scientific knowledge as we measure it to-day, his hypothesis was a wonderful forestalling of present views.
It is quite obvious that the views of Liebig, if true, admit of easy proof; since, if the energy of muscular power comes from the breaking down of proteid, there should be a certain parallelism between the output of nitrogen from the body and the amount of muscular work accomplished, everything else being equal. As stated in a previous chapter, such study of this question as was made soon disclosed the fact that the one element above all others that seemed to influence the output of nitrogen was the intake of proteid food. Thus, the English investigators, Lawes and Gilbert, found by experimenting with animals that when the latter were kept under uniform conditions of muscular work, the amount of nitrogen excreted ran parallel with the intake of nitrogen. Further, in the early experiments of Voit, the results obtained clearly showed that variations in the amount of work performed were practically without influence on the excretion of nitrogenous waste products.
The experiment, however, that came as a death blow to the theories of Liebig was that of Fick and Wislicenus,[43] who in 1865 made an ascent of the Faulhorn, 6500 feet high, using a diet wholly non-nitrogenous. From the nitrogen excreted they were able, of course, to calculate the amount of proteid oxidized in the body during the period of work, and found that the proteid consumed could not have furnished, at the most, more than one-half the energy required to lift the weights of their bodies to the top of the high peak. Further, they observed that neither during the work period, nor immediately after, was there any noticeable increase in the excretion of nitrogen. Obviously, as they state, the oxidation of proteid matter in the body cannot be the exclusive source of the energy of muscular contraction, since the measurable amount of external work performed in the ascent of the mountain was far greater than the equivalent of the energy capable of being furnished by the proteid actually burned. To which may be added the fact that considerable energy, not measurable in their experiment, must have been employed in the work of the involuntary muscles of the body; thus increasing by so much the difference between the muscular work actually accomplished and the available energy from proteid consumed. It is true that minor criticisms regarding certain details of the experiment can be offered to-day, such as the fact that the men were, in a measure, in a state of “nitrogen starvation,” etc., but these criticisms do not in any degree militate against the main thesis that the energy of muscular contraction does not come exclusively from the consumption or breaking down of proteid, either of food or tissue. Vigorous and even severe muscular work does not necessarily increase the decomposition of proteid material. Dogs made to run in large treadmills, with the same diet as on resting days, were found to excrete practically no more nitrogen than during the days of rest. Occasionally, however, in some one experiment the output of nitrogen would show an increase over the output on resting days. Further, experiments made with horses led to essentially the same result, except that greater increase in the excretion of nitrogen was observed than with dogs. This increase in nitrogen output, however, as a concomitant of increased muscular activity, could be prevented by adding to the amount of carbohydrate food.
While experiments of this nature, on man and animals, all tended to show little or no increase in the excretion of nitrogen, as a result of muscle work; and likewise no increase in the output of sulphur and phosphorus, thus strengthening the view that muscular energy is not the result of proteid disintegration, there was observed marked increase in the consumption of oxygen, and in the excretion of carbon dioxide. Non-nitrogenous matter was thus at once suggested as the material with which muscle chiefly does its work. There is to-day no question of the general truth of this statement, yet there are other aspects of the problem to be considered before we can lay it aside. Pflüger, working with dogs, and Argutinsky, experimenting on himself by arduous mountain climbing, reached conclusions seemingly quite opposed to what has just been said. Their results, however, admit of quite a different interpretation from what they were disposed to attach to them. Thus, Pflüger[44] would go back to the old view that all muscle work is at the expense of proteid material, because lean dogs fed mainly, or entirely, on meat and made to do an excessive amount of work were found by him to excrete nitrogen somewhat in proportion to the amount of work done. Argutinsky,[45] likewise, in his mountain climbing carried to the point of fatigue, and with a high proteid intake likewise, saw in the increased output of nitrogen a suggestion of the same idea. In reality, however, their results merely prove that, under some circumstances, proteid may serve as the chief source of muscular energy; as when the body is poor in fat and carbohydrate, or when the intake consists solely of proteid matter. In other words, muscular work may result in an increased excretion of nitrogen when the work is very severe, and there is not a corresponding increase in the fats or carbohydrates (fuel ingredients) of the food. In the words of Bunge,[46] “we might assume à priori, on teleological grounds, that in the performance of its most important functions the organism is to a certain extent independent of the quality of its food. As long as non-nitrogenous food is supplied in adequate quantity or is stored up in the tissues, muscular work is chiefly maintained from this store. When it is gone the proteids are attacked.”
There is no question that the energy of muscular contraction can come from all three classes of organic foodstuffs. Voluntary muscular movement is under the control of the nervous system, and when the stimulus is applied the muscle is bound to contract, provided of course there is sufficient energy-containing material present to furnish the means. Muscle tissue, like other tissues and organs, has a certain power of adaptability, by which it is able to do its work, even though it is not adequately supplied with its preferred nutrient. While proteid is plainly not the material from which the energy of muscular contraction is ordinarily derived, it is equally evident that in emergency, as when the usual store of carbohydrate and fat is wanting, proteid can be drawn upon, and in such cases vigorous work may be attended with increased nitrogen output. In harmony with this statement, we find on record in recent years many experiments, both with man and animals, where severe muscular labor is accompanied by an excretion of nitrogen beyond what occurs on days of rest; but by simply adding to the intake of non-nitrogenous food this increased outgo of nitrogen is at once checked. With moderate work, the nitrogen outgo is rarely influenced; it is only when the work becomes excessive, or the store of non-nitrogenous reserve is small and the intake of the latter food is limited, that proteid matter is drawn upon to supply the required energy.
Recalling what has been said regarding the significance of the respiratory quotient, it is obvious that we have here a means of acquiring information as to the character of the material that is burned up in the body during muscular work. Increased metabolism of carbohydrate will necessarily result in raising the respiratory quotient, and if the latter food material alone is involved the respiratory quotient must naturally approach 1.0. Zuntz, however, has clearly shown that vigorous muscular activity does not materially change the respiratory quotient; except in cases of very severe work, where the oxygen-supply of the muscles is interfered with. Indeed, the muscles may be made to do work sufficient to increase the consumption of oxygen threefold or more, without any change in the respiratory quotient being observed. And as there is frequently no change whatever in the output of nitrogen under these conditions, it follows that the energy of the muscle work must have come from the decomposition of non-nitrogenous material. If carbohydrates alone were involved, the respiratory quotient would obviously undergo change. Since, however, this remains practically stationary, we are led to the conclusion that fat must be involved in large degree, in addition to carbohydrate.
In this connection, it is a significant fact that with fasting animals, where the store of carbohydrate material is more or less used up, severe muscle work may be accomplished without any appreciable increase in nitrogen output, thus showing that proteid material is not involved and clearly pointing to fat as the source of the muscular energy. Thus, in an experiment referred to by Leathes, a dog on the sixth and seventh day of starvation was made to do work in a treadmill equivalent to climbing to a height of 1400 meters, yet the output of nitrogen was increased from six to only six and a half grams. Obviously, not much of the energy of this muscle work could have come from the breaking down of proteid, but it must have been derived mainly from the oxidation of fat. There is abundant evidence that fat can be used as a source of energy by muscles, as well as carbohydrates and proteids, and there is every reason for believing that the yield of work for a given amount of chemical energy in the form of fat is as good as in the case of either of the other two substances. In fact, the observations of Zuntz show that fat can be used just as economically by the body for muscle work as either carbohydrates or proteid. Thus, in one experiment,[47] he determined the oxygen-consumption and respiratory quotient in a man resting and working on three different diets—one principally fat, one principally carbohydrate, and the other principally proteid—and found that slightly less oxygen and energy were required to do work on the fat diet than on the others. This is clearly shown in the following table:
| Diet Principally. | Resting. | Working. | Kilo- | Per Kilogram-meter | |||
|---|---|---|---|---|---|---|---|
| Oxygen Used per Minute. | Respira- | Oxygen | Respira- | Oxygen | Calories. | ||
c.c. | c.c. | c.c. | |||||
| Fat | 319 | 0.72 | 1029 | 0.72 | 354 | 2.01 | 9.39 |
| Carbohydrate | 277 | 0.90 | 1029 | 0.90 | 346 | 2.17 | 10.41 |
| Proteid | 306 | 0.80 | 1127 | 0.80 | 345 | 2.38 | 11.35 |
From these data, we see that per kilogram-meter of work less energy was required and less oxygen consumed with fat than with either of the other two foodstuffs; but practically, fat and carbohydrate as sources of muscle energy have about the same value.
Much stress is ordinarily laid upon the importance of a large intake of proteid food whenever the body is called upon to perform severe, or long-continued, muscular work; but in view of what has been stated it may be questioned whether there is any real physiological justification for such custom. The pedestrian Weston,[48] who in 1884 walked 50 miles a day for 100 consecutive days, was found by Blyth during a period of five days to consume in his food 37.2 grams of nitrogen a day, while he excreted only 35.3 grams, leaving a balance of 1.9 grams of nitrogen per day apparently stored in the body. His daily food during this period was composed of 262 grams of proteid, 64.6 grams of fat, and 799 grams of carbohydrate, with an estimated fuel value of 4850 calories. Yet he performed this large amount of work daily, and still laid by a certain amount of proteid on a ration, the energy value of which would not ordinarily be considered high for the muscular work to be done. Fourteen years prior to this, Weston, while in New York, was carefully studied by Dr. Flint during a period of 15 days, on 5 of which he walked a total of 317 miles. His diet was essentially a proteid diet, consisting principally of beef extract, oatmeal gruel, and raw eggs. Nitrogen intake and output were carefully compared during the days of rest and during the days of work, with the results tabulated.
Period. | Occupation. | Duration | Nitrogen. | ||||
|---|---|---|---|---|---|---|---|
In | In | In | Gain + | ||||
days | grams | grams | grams | grams | |||
| Fore period | Comparative rest | 5 | 22.0 | 18.7 | 1.4 | +1.9 | |
| Working period | Walking 62 miles per day |  | 5 | 13.2 | 21.6 | 1.6 | –10.0 |
| After period | Rest | 5 | 28.6 | 22.0 | 2.2 | +4.4 | |
In this case it will be noted that the daily ration was comparatively small, and, further, that during the working period the subject consumed much less proteid than on the resting days. Moreover, when we remember that the total energy value of his diet must have been quite small, it is not at all strange that in the laborious task of walking 62 miles a day he should have temporarily drawn upon his store of body proteid to the extent of 62.5 grams, or 10 grams of nitrogen a day. Such experiences, however, do not by any means constitute proof that in excessive muscular work there is need for the consumption of correspondingly increased quantities of proteid food, or that the energy of muscular work comes preferably from the breaking down of proteid material. Carbohydrate and fat unquestionably take precedence over proteid in this respect, and we may accept as settled the view that in all practical ways carbohydrate and fat stand on an equal footing as sources of muscular energy. Less clear, perhaps, is the question as to how these two radically different types of organic material are utilized by the muscle. It has been a favorite belief among some physiologists that the contracting muscle makes use of only one substance as the direct source of its energy, and that this substance is the sugar dextrose. This view would seemingly imply that fat and proteid must undergo alteration prior to their utilization by the muscle; that, possibly, the carbon of the fat and proteid is transformed into sugar before the muscle can make use of it. So far as fat is concerned, this view is not supported by the facts available, since experiments show that the heat and energy liberated in the utilization of a given amount of fat in muscle work are in harmony with the energy value of the fat; in other words, the fat is apparently burned, or oxidized, directly, without undergoing previous transformation into any form of carbohydrate; or, if transformation does occur, under some conditions, it must take place within the muscle and without loss of energy. The practical significance of these facts is at once apparent, for if fat, in order to be available as a source of muscle energy, must first undergo conversion into sugar, it would be far more economical from a physiological standpoint to replace the fat of the diet with carbohydrate in any attempt to provide suitable nourishment for the working muscle. We may safely conclude, however, that fat and carbohydrate, as previously suggested, are in reality both capable of direct metabolism by the muscular tissue, and that each is of value as a source of muscular energy in proportion to its heat of combustion, yielding substantially the same proportion of its potential energy in the form of mechanical work.
Regarding the utilization of proteid as a source of energy by the muscle, there are many grounds for believing that here the body has to deal with certain alterations, before the proteid can be made available. We may indeed conjecture the transformation of a non-nitrogenous portion of the proteid molecule into carbohydrate, as a necessary step in its utilization for muscle work. It is certainly true that in the ordinary katabolic processes, through which proteid passes, there is a tendency for the nitrogen-containing portion to be quickly split off and eliminated, leaving a carbonaceous residue which may represent as much as 80 per cent of the total energy of the original proteid. This so-called carbon moiety of the proteid molecule is apparently much less rapidly oxidized than the nitrogenous portion, and may indeed be temporarily stored in the body, in the form of fat or carbohydrate.[49] We have very convincing proof that the carbohydrate glycogen can be formed from proteid. Thus, the feeding of proteid to warm-blooded animals may be accompanied by an accumulation of glycogen in the liver. This is interpreted as meaning that in the cleavage of proteid by digestion the various nitrogenous products formed are somewhere, probably in the liver, still further acted upon; the contained nitrogen with some of the carbon being converted into urea, while the non-nitrogenous residue is transformed into glycogen, or sugar. That some such change takes place, or, more specifically, that carbohydrate does result from proteid is more strikingly shown in human beings suffering with diabetes. In severe forms of this disease, all carbohydrate food consumed is rapidly eliminated through the kidneys in the form of sugar, the body having lost the power of burning sugar. If such a person is placed upon a diet composed exclusively of proteid, sugar still continues to be excreted, and there is observed a certain definite relationship between the nitrogen output and the excretion of sugar, thus implying that they have a common origin.
Further, there are certain drugs, such as phloridzin, which, when introduced into the circulation, set up a severe diabetes and glycosuria. Dogs treated in this way, fed solely on proteid or even starved for some time, will continue to excrete sugar, and as in the previous instance, there is observed a certain definite ratio between the nitrogen output and the elimination of sugar; thus leading to the conclusion that both arise from the destruction of the proteid molecule. Careful study of this ratio of dextrose to nitrogen has led Lusk to the conclusion that full 58 per cent of the proteid may undergo conversion into sugar in the body. Hence, it is easy to see how in muscle work, when proteid is the sole source of the energy of muscular contraction, the work accomplished may still result from the direct oxidation of carbohydrate material, indirectly derived from the proteid molecule. It requires no argument, however, to convince one that such a procedure for the normal individual is less economical physiologically than a direct utilization of carbohydrate and fat, introduced as such and duly incorporated with the muscle substance. Consequently, in the nourishment of the body for vigorous muscular work, there is reason in a diet which shall provide an abundance of carbohydrate and fat; proteid being added thereto only in amounts sufficient to meet the ordinary requirements of the body for nitrogen and to furnish, it may be, proper pabulum for the development of fresh muscle fibres, where, as in training, effort is being made to strengthen the muscle tissue and so enable it to do more work. Increase in proteid food may help to make new tissue, but the source of the energy of muscle work is to be found mainly in the breaking down of the non-nitrogenous materials, carbohydrate and fat.
In view of these facts, we may advantageously consider next the real significance of the proteid metabolism of the body. As we have seen, a meal rich in proteid leads at once—within a few hours—to an excretion of urea equivalent to full 50 per cent of the nitrogen of the ingested proteid, while a few hours later finds practically all of the nitrogen of the intake eliminated from the body. Further, it is to be remembered that in a general way this occurs no matter what the condition of the body may be at the time and no matter how large or small the amount of proteid consumed. In other words, there is practically no appreciable storing of nitrogen or proteid for future needs,—at least none that is proportional to the increase in nitrogen intake, even though the body be in a condition approximating to nitrogen starvation. Moreover, it is to be recalled that the increased proteid metabolism attendant on increased intake of proteid food is accompanied by an acceleration of the metabolism of non-nitrogenous matter; thus resulting in a stirring up of tissue change, with consequent oxidation and loss of a certain proportion of accumulated fat and carbohydrate. Coincident with this increased excretion of nitrogen, the output of carbon dioxide is likewise increased somewhat, due as is believed mainly to increased metabolism of the involuntary muscle fibres of the gastro-intestinal tract, by action of which the accelerated peristalsis so characteristic of food intake is accomplished. Further, the increased output of carbon dioxide, under these conditions, is to be attributed also to the greater activity of the digestive and excretory organs, naturally stimulated to greater functional power by the presence of proteid foods and their decomposition products. Still, as stated by Leathes, “the two main end-products of proteid metabolism, urea and carbonic acid, are, to a great extent, produced independently of each other, and the reactions which result in the discharge of the nitrogen are not those in which energy is set free, work done, and carbonic acid produced.” In other words, there is suggested what we have already referred to, viz., that in proteid metabolism a nitrogenous portion of the proteid molecule is quickly split off and gotten rid of, while the non-nitrogenous part may be reserved for future oxidation, serving as a source of muscle energy or for other purposes. This being so, it is plain that “proteid metabolism in so far as it is concerned with the evolution of energy, proteid metabolism in its exothermic stages, may be almost entirely non-nitrogenous metabolism” (Leathes).
Is there any advantage to the body, however, in this carbonaceous residue of the proteid molecule over simple carbohydrate and fat? Can the processes of the body be accomplished more economically, or more advantageously, with a daily diet so constructed that the tissues and organs must depend mainly upon this carbon moiety of the proteid molecule for their energy-yielding material? It has been one of the physiological dogmas of the past, that the tissues and organs of the body, or rather their constituent cells, preferred to use proteid for all their needs whenever it was available. If proteid were wanting, either because of insufficient intake, or because of excessive activity, then the tissue cells would draw upon their store of non-nitrogenous material. Food proteid and tissue proteid, however, were the materials preferred by the organism, so ran the argument, and the large and incessant output of nitrogen which accompanied the intake of proteid was accepted as proof of the general truth of this idea. We might well question wherein lies the great advantage to the body in this continual excretion of nitrogen; whether the loss of energy in handling and removing the nitrogenous portion of the necessarily large proteid intake, in order to render available the non-nitrogenous part of the molecule, might not more than compensate for the supposed gain? But the truly astonishing fact that the output of nitrogen runs parallel with the intake of proteid, that the body cannot store up nitrogen to any large extent, has been taken as conclusive evidence that the organism prefers to use proteid for all of its requirements. Truly, we might just as well argue that this significant rise in the excretion of nitrogen after partaking of a proteid meal is an indication that the body has no need of this excess of nitrogen; that it is indeed a possible source of danger, since the system strives vigorously to rid itself of the surplus, and that the energy-needs of the body can be much more advantageously and economically met from fat and carbohydrate than from the carbonaceous residue resulting from the disruption of the proteid molecule.
In discussing these questions, we shall need to refer to several of the current theories concerning proteid metabolism, notably, the theories of Voit, Pflüger, and Folin. In 1867 Carl Voit,[50] of Munich, advanced the view that the proteid material of the body exists in two distinct forms, viz., as “morphotic” or “organized” proteid, representing proteid which has actually become a part of the living units of the body, i. e., an integral part of the living tissues; and “circulating” proteid, or that which exists in the internal meshes of the tissue, or in the surrounding lymph and circulating blood. The real point of distinction here is that while one portion of the body proteid is raised to the higher plane of living matter, i. e., becomes a component part of the living protoplasm, another and perhaps larger portion is outside of the morphological framework of the tissue, constituting a sort of internal medium which bathes the living cells, and acts as middleman between the blood and lymph on the one side and the living cells on the other. According to Voit’s view, it is this circulating proteid that undergoes metabolism; the proteid of the food after digestion and absorption being carried to the different tissues and organs, and then, without becoming an integral part of the living protoplasm of the cells, it is broken down under the influence of the latter. Obviously, small numbers of tissue cells are constantly dying, their proteid matter passing into solution, where it likewise undergoes metabolism. In other words, according to Voit, the great bulk of the proteid undergoing katabolism is the circulating proteid, derived more or less directly from the food, and which at no time has been a part of the tissue framework; while a smaller, but more constant amount, represents the breaking down of tissue cells. This conception of proteid metabolism is akin to our conception of morphological and physiological destruction. In the words of Foster: “We know that an epithelial cell, as notably in the case of the skin, may be bodily cast off and its place filled by a new cell; and probably a similar disappearance of and renewal of histological units takes place in all the tissues of the body to a variable extent. But in the adult body these histological transformations are, in the cases of most of the tissues, slow and infrequent. A muscle, for instance, may suffer very considerable wasting and recover from that wasting without any loss or renewal of its elementary fibres. And it is obvious that the metabolism of which we are now speaking does not involve any such shifting of histological units. On the other hand, we find these histological units, the muscle fibre or the gland cell, for instance, living on their internal medium, the blood, or rather on the lymph, which is the middleman between themselves and the actual blood flowing in the vascular channels.”
Voit claims that the proteid dissolved in the fluids of the body is more easily decomposable than that which exists combined in organized form, or as more or less insoluble tissue proteid; and it is this soluble and circulating form which, under the influence of the living cells, undergoes destruction or metabolism. We know, as has been previously stated, that oxidation does not take place to any extent in the circulating blood, and similarly there is every reason for believing that proteid metabolism does not occur in this menstrum. Metabolism is limited mainly to the active tissues of the body, but according to the present conception of the matter it does not occur at the expense of the proteid of the living cells, but involves material contained in the fluids bathing the cells; i. e., it is not the organized proteid that undergoes metabolism, but the proteid circulating in and about the internal meshes of the cells and tissues, the living cell being the active agent in controlling the process. Further, this view lessens the difficulty of understanding the elimination of nitrogen after a meal rich in proteid. If it was necessary to assume that all the proteid of our daily food is built up into living protoplasm before katabolism occurs, it would be exceedingly difficult to explain the sudden and rapid elimination of nitrogen which follows the ingestion of proteid. For example, we can hardly imagine that merely eating an excess of proteid food will lead to an actual breaking down of the living framework of the tissues, equivalent to the amount of nitrogen which the body at once eliminates. Voit’s theory, on the other hand, supposes a twofold origin of the nitrogen excreted; one part, the larger and variable portion, comes from the direct metabolism of the circulating proteid, being the immediate result of the ingested food and varying in amount with the quantity of proteid food consumed; the other, smaller and less variable in amount, has its origin in the metabolism of the true tissue proteid, or the actual living framework of the body.
In a fasting animal, the tissues and organs of the body still contain a large proportion of proteid matter, yet only a small fraction of this proteid is eliminated each day, hardly 1 per cent. If, however, proteid is absorbed from the intestine, proteid metabolism is at once increased, and the excretion of nitrogen may be fifteen times greater than during hunger. In other words, the extent of proteid metabolism is not at all proportional to the total amount of proteid contained in the body as a whole, but runs parallel in a general way with the quantity of proteid absorbed from the intestine. Obviously, the newly absorbed proteid is quite different in nature from the proteid which in much larger amounts is deposited throughout the body, since it is not organized and is so much more easily decomposable (Voit). This is the circulating proteid of the body; it exists in solution, and it is a significant fact that, according to Voit, the chemical transformations that characterize proteid katabolism occur only in solution. The organized proteid, on the other hand, is in a state of suspension, and its katabolism, which is relatively very small, is preceded by solution of the proteid in the fluids of the tissue, after which its further breaking down is assumed to be the same as that of the circulating proteid. This latter view is a fundamental part of the Voit theory; in long-continued fasting, for example, the living protoplasm of the various tissues and organs is of necessity drawn upon for the nourishment of the more vital parts of the body, such as the brain, spinal cord, etc., consequently the organized proteid is gradually dissolved and then decomposed, after it has become liquefied and has thus lost its organized structure.
In this conception of proteid metabolism, we picture the different organs and tissues of the body as being permeated by a fluid which carries variable amounts of nutritive material, the quantity of the latter determining in a way the extent of the proteid katabolism which shall take place. As the proteid of the food passes into the blood and lymph, the fluids bathing the cells are correspondingly enriched, and as a result, proteid katabolism is accelerated in parallel degree. During hunger, on the other hand, the organized proteid of the tissue cells is gradually liquefied and passes out into the current of the circulating fluids. As before stated, the organized proteid as such is never decomposed; it must first enter into solution, and then under the influence of the living cells it undergoes disruption in the same manner as the circulating proteid. It is thus evident that the tissue cells and the circulating fluids permeating them bear an ever changing relationship to each other. Excess of circulating proteid will be attended by increased katabolism, while at the same time there may be some accumulation of proteid in the cells, and indeed some conversion into organized proteid. During fasting, hunger, or with an insufficient intake of proteid food, the current will naturally be in the opposite direction, and organized proteid will slowly, but surely, be drawn upon.
Again, we may ask in view of these facts, of what real use to the body is this large katabolism of circulating proteid? We can easily understand the need of proteid to supply the loss incidental to the breaking down of organized or true tissue proteid, but this we are led to believe is very small in amount. Is there any real need for proteid beyond this requirement? The physiological fuel value of proteid is no greater than that of carbohydrate and considerably less than half that of fat, consequently there is on the surface no apparent reason why proteid should be used for its energy value in preference to the non-nitrogenous foodstuffs. Further, as we have seen, the energy of muscle work comes mainly, at least, from the breaking down of fat and carbohydrate; proteid, in the case of the well-nourished individual, ordinarily playing no part in this important line of energy exchange. Lastly, in the katabolism of proteid there is the large proportion of nitrogenous matter to be split off and disposed of before the carbon moiety of the molecule can be rendered available. Here, we have involved not only a loss of energy, but in addition a certain amount of what appears to be useless labor thrown upon the liver, kidneys, and other organs. Is there any wonder that the thoughtful physiologist, looking at the facts and theories presented by the Voit conception of proteid katabolism, should ask wherein lies the value to the body of this high rate of metabolism of circulating proteid, a rate of metabolism which is seemingly governed primarily by the amount of proteid food ingested?
Turning next to Pflüger’s[51] views regarding proteid katabolism, we find a totally different outlook. Here, the supposition prevails that the plasma of the blood and lymph, with its contained proteid, is the food of the organs or their cells, but that before this food material can undergo katabolism it must first be absorbed by the cell and built up into the living protoplasm of the tissue. In other words, according to the views expressed by Pflüger, katabolism must be preceded by organization of the proteid. Expressed in still different language, the proteid material circulating in blood and lymph must be eaten up by the hungry cells and, by appropriate anabolic processes, made an integral part of the living protoplasm before disassimilation can occur. Further, according to Pflüger’s conception of these processes, there is a radical difference in the chemical nature of living protoplasm as compared with that of the so-called circulating proteid. The latter is looked upon as being comparatively stable, resisting oxidation in high degree, and hence not prone to undergo metabolism. Living protoplasm, on the other hand, is characterized by instability, suffering oxidation with the greatest ease, and hence readily broken down in the ordinary processes of katabolism. Assuming for the moment the correctness of this theory, we see at a glance that all disruption of proteid matter in the body must be preceded by the upbuilding of the proteid into living protoplasm. There can be no destruction of proteid until the latter has been raised to the high plane of living matter. The dead, inert circulating proteid can serve simply as food for the living cells, and cannot undergo katabolism until it has been built up into the organized structure of the tissue or organ. Even though we grant that a small proportion of proteid may suffer katabolism without previous organization, it does not materially modify the general trend of the argument that, according to Pflüger’s hypothesis, proteid katabolism is essentially a process involving the disruption of living protoplasm.
Consider what this means in the light of facts already presented. Remembering that the one factor above all others influencing the rate of proteid katabolism is the amount of proteid food taken in, and that the output of nitrogen, no matter what the previous condition of the body or the amount of proteid food ingested, runs more or less parallel with the consumption of proteid, we are forced to the conclusion, in accepting this hypothesis, that there must be superhuman activity in the building up of living protoplasm, only to be followed, however, by its immediate and more or less complete breaking down. Further, think of the daily or periodical fluctuation in the construction of bioplasm, coincident with variations in the amount of proteid food consumed, and the corresponding destruction of bioplasm as indicated by the daily output of nitrogen. Imagine, if you will, the concrete case of a man of 70 kilos body-weight eating a daily ration containing 125 grams of proteid, the nitrogen equivalent of which is practically excreted within twenty-four hours, and are we not wise in hesitating to believe that all of that proteid has been so quickly built up into living or organized tissue only to be immediately broken down and thrown out of the body? Think of the enormous activity implied in the manufacture of this bioplasm in the time allotted, and for what? Apparently, so that it can be broken down again. But such energy as is liberated in the breaking-down process might be derived far more economically by simple destruction of the proteid, as contained in the meshes of the tissue elements, without assuming a preliminary conversion into living protoplasm. Obviously, we have here a theory which does not help us in arriving at any very satisfactory conception of proteid metabolism. The facts which Pflüger and his followers bring forward in support of the theory are not very convincing, or at least not sufficiently so to carry conviction in the face of a natural disinclination to believe in the necessity of such a profound anabolic process, merely as a prelude to the speedy destruction of the finished product. Finally, we may add that if all proteid katabolized in the body must first be raised to the high level of living protoplasm before the final disruption can occur, it may be prudent to keep the daily intake of this foodstuff down to a level somewhat commensurate with the real needs of the body.
As has been stated many times in the course of this presentation, the most striking feature of proteid metabolism is the rapidity with which large quantities of proteid consumed as food are broken down, and the contained nitrogen eliminated from the body as urea. A few hours will suffice to accomplish the more or less complete destruction of food proteid; and any theory of proteid metabolism, to be at all satisfactory, must explain this peculiar phenomenon. According to recent investigations, it seems probable that some, at least, of the cleavage products of proteid formed during intestinal digestion are not built up into new proteid, but are at once eliminated mainly in the form of urea, without becoming a part of either the so-called circulating proteid, or the living protoplasm of the body. It will be recalled that under the influence of the digestive enzymes, trypsin and erepsin, proteid foodstuffs may be broken down while undergoing intestinal digestion into monamino- and diamino-acids, such as leucin, tyrosin, arginin, lysin, etc. A certain proportion of these comparatively simple substances may be directly absorbed by the portal circulation and carried to the liver, where they may undergo conversion into urea. In this way, some portion of the nitrogen of the ingested food may be quickly eliminated from the system. As has been stated in another connection, we are not sure at present how far proteid decomposition of the kind indicated takes place normally in the body. We merely know that there are present in the intestine, enzymes capable of splitting up proteid into these small fragments, and that substances of this type when made to circulate through the liver are transformed into urea. These facts, coupled with the well-known tendency of the nitrogen of proteid food to appear in the excretions a few hours after the food in question has been consumed, naturally suggests a direct breaking down of proteid along the lines indicated, with a possible retention of a carbonaceous residue (nitrogen-free) for subsequent oxidation, as a source of energy for heat or work. Obviously, all of the proteid food cannot behave in this manner, for if such were the case there would be no proteid available for making good the normal waste incidental to tissue changes. Either a certain amount of proteid escapes this profound alteration produced by the proteolytic enzymes in question, or else a certain proportion of these simple decomposition products is synthesized in the intestine, or in the tissues of the body, to form new proteid for the regeneration of cell protoplasm. However this may be, we have presented in this view a plausible explanation of the prompt appearance of food nitrogen in the excretions, and without compelling belief in a theory, such as Pflüger’s, which taxes one’s credulity to the utmost. To be sure, as a prominent writer on physiology has recently said, such a view stands opposed to our conceptions of the importance of proteid food; but it seems possible, in the light of accumulating knowledge, that our conceptions of the part played by proteid foods in the nutrition of man have not been strictly logical, or quite in accord with true physiological reasoning.
Again, in this connection, we may ask the question, why is it that the body provides such an effective method for the speedy breaking down of proteid food and the prompt elimination of the contained nitrogen? Whatever the means made use of by the organism in accomplishing this, the result is the same; the nitrogen of the ingested food is, in large measure, quickly gotten rid of. We clearly recognize the all-important position of proteid foods in the nutrition of the body, but there appears a certain inconsistency in this prompt removal of the nitrogen-containing portion of the proteid molecule. The nitrogenous part of the proteid food is, physiologically considered, the all-important part. It is the only source of nitrogen available to the system, and yet apparently the larger proportion of this nitrogenous material is not utilized in any recognizable way, but is eliminated as quickly as possible. Is it not within the limits of possibility that these methods, whatever may be the exact mechanism involved, are merely a means of getting rid of a surplus of proteid for which the body has no real need? This question I shall try to answer later on in another connection, but we may advantageously keep this possibility in mind while we are discussing these theories of proteid metabolism.
It is obvious, in the light of present knowledge, that there must be a certain amount of true tissue proteid broken down each day, independent of that larger metabolism coincident with the intake of proteid food. However much this more voluminous proteid katabolism may fluctuate, owing to variations in the intake of proteid, and whatever the significance of this latter phase of metabolism, it is self-evident that there must be a steady, constant metabolism, upon which the life of the various tissues and organs of the body depends, and by which the proteid integrity of the tissue cells is maintained. This implies a certain degree of true tissue change, in which definite amounts of proteid material are broken down and the resultant loss made good from the proteid intake. No matter what specific name be applied to this form of proteid katabolism, its existence is clearly recognized. It is obviously a form of metabolism distinct, and probably quite different, from that form, more variable in extent, which is associated with the intake of proteid food. Plainly, if there is truth in these statements, there should be some data available by means of which these two lines of proteid katabolism can be more or less sharply differentiated.
Thanks especially to the work of Folin,[52] these data are now apparently at hand, and the facts which he has accumulated with painstaking care seem destined to throw additional light upon our conception of proteid metabolism. It will be remembered that in the breaking down of proteid, the great bulk of its contained nitrogen is eliminated in the form of urea. In addition, a certain smaller amount of nitrogen is excreted in the forms of creatinin and uric acid. As we have seen, the total output of nitrogen, which measures the extent to which proteid is decomposed in the body, varies with the intake of proteid food; but it is found that the proportion of nitrogen excreted in the forms of urea and uric acid varies with the extent of the metabolism. In other words, quantitative changes in the daily proteid katabolism are accompanied by pronounced changes in the distribution of the excreted nitrogen. Let us take a single illustration from Folin’s results; the case of a healthy man who on one day—July 13—consumed a proteid-rich diet, and on the other day—July 20—was living on a diet containing only about 1 gram of nitrogen. The composition of the excretion through the kidneys on these two days is shown in the following table:
| July 13. | July 20. | |
|---|---|---|
| Volume of urine | 1170 c.c. | 385 c.c. |
| Total nitrogen | 16.80 grams | 3.60 grams |
| Urea-nitrogen | 14.70 " = 87.5% | 2.20 " = 61.7% |
| Uric acid-nitrogen | 0.18 " = 1.1% | 0.09 " = 2.5% |
| Creatinin-nitrogen | 0.58 " = 3.6% | 0.60 " =17.2% |
Here we see, as would be expected, that on the high proteid diet, there was a large excretion of total nitrogen and of urea; while on the low proteid diet, nitrogen and urea were correspondingly diminished. The point to attract our attention, however, is the marked difference in the percentage of urea-nitrogen in the two cases; a difference which amounts to about 26 per cent. A similar difference is to be noted in the percentage of uric acid-nitrogen. Lastly, it is to be observed that in spite of the great difference in the extent of metabolism on the two days—an excretion of 16.8 grams of nitrogen, as contrasted with 3.6 grams—the amount of creatinin-nitrogen is essentially the same. Folin finds that these peculiarities in the percentage distribution of excreted nitrogen hold good in all cases where there is this wide divergence in the amount of proteid katabolized, and, further, that there is a gradual and regular transition from the one extreme to the other. He sees in these results evidence that there are in the body two forms of proteid katabolism, essentially independent and quite different. One kind is extremely variable in quantity, while the other tends to remain constant. The variable form has its own particular kind of waste products, of which urea is the chief. The constant katabolism, on the other hand, is largely represented by creatinin and to a lesser degree by uric acid. The more the total katabolism is reduced, the more prominent become creatinin and uric acid, products of the constant katabolism; while urea, as chief representative of the variable katabolism, becomes less conspicuous. Folin suggests the term endogenous or tissue metabolism for the constant variety, while the variable form he would name exogenous or intermediate metabolism.
In these suggestions we have not theory only, but a number of very important facts which plainly must have some significance. Take, for example, the excretion of creatinin. It is a characteristic nitrogenous waste product, but its elimination from the body is wholly independent of quantitative changes in the total amount of nitrogen excreted. In other words, the amount of creatinin eliminated is a constant quantity for a given individual under ordinary conditions, no matter how great the variation in the amount of proteid food, provided no meat is eaten. Meat must be avoided in testing this point, since meat contains a certain amount of creatin, or other components, which would be excreted as creatinin. Further, it is found that every individual has his own specific creatinin excretion, which fact again emphasizes the idea that this substance is a product of true tissue katabolism, having no connection with that variable metabolism, of which urea is the striking representative. These are facts which cannot be ignored. They are well established by the careful observations of Folin, and they are confirmed by a large number of observations made in our own laboratory. Turn now to that other, more conspicuous, product of proteid katabolism, urea. With a so-called average proteid intake, about 88–90 per cent of the excreted nitrogen will be in the form of urea, but, as Folin states, “with every decided diminution in the quantity of total nitrogen eliminated, there is a pronounced reduction in the per cent of that nitrogen represented by urea. When the daily total nitrogen elimination has been reduced to 3 grams or 4 grams, about 60 per cent of it only is in the form of urea.” Here, we have the chief product of exogenous metabolism, a substance quite distinct from creatinin, just as the process by which it originates is likewise quite distinct.
Exogenous metabolism is plainly a process of quite a different order from that of endogenous, or tissue metabolism. The latter involves oxidation, while the former consists essentially of a series of hydrolytic cleavages which result in a rapid elimination of the proteid-nitrogen as urea. In this conception of exogenous katabolism, we have essentially the same viewpoint as was previously taken in attempting to explain how excess of proteid food can be so quickly decomposed, and its nitrogen removed from the body. Whether the hydrolytic cleavage is accomplished solely by trypsin and erepsin, whether it takes place only in the intestine and in the liver, or whether other glands and tissues are involved, is at present immaterial; the essential point is that we have in the body a variety of proteid katabolism, quite different from true tissue katabolism, the extent of which is dependent primarily upon the amount of proteid food consumed. The process involved is one which aims at the rapid removal of the proteid-nitrogen as urea; without incorporation of the absorbed proteid, or its decomposition products, either as an integral or adherent part of the tissue proteid. Hydrolytic cleavage is eminently fitted to accomplish this with the least expenditure of energy, while the carbonaceous residue of the proteid thus freed from nitrogen can be transformed into carbohydrate, or directly oxidized as the needs of the body demand.
As one considers these views so admirably worked out by Folin, the question naturally arises, if the real demands of the body for proteid food will not be adequately met by the quantity necessary to satisfy the true tissue metabolism? We may well believe, with Folin, that “only a small amount of proteid, namely, that necessary for the endogenous metabolism, is needed. The greater part of the proteid furnished with so-called standard diets, like Voit’s, i. e., that part representing the exogenous metabolism, is not needed; or, to be more specific, its nitrogen is not needed. The organism has developed special facilities for getting rid of such excess of nitrogen, so as to get the use of the carbonaceous part of the proteid containing it.” In endogenous metabolism, we have a steady, constant process quite independent of the amount of proteid food, and absolutely indispensable for the maintenance of life. So far as we know at present, its representative creatinin is, for a given individual, the same in amount during fasting as when a rich, meat-free, proteid diet is taken. The one factor that seemingly determines the amount of creatinin eliminated is the weight of the individual, or more exactly the weight of the true tissue elements of the body, as distinct from fat or adipose tissue. Endogenous or tissue katabolism obviously calls for a certain quantity of proteid to maintain equilibrium, but this is small in amount as compared with the usual intake of proteid foods. The average man, with his ordinary dietetic habits, consumes more nitrogen than the body can possibly make use of. The excess is not stored up, “because the actual need of nitrogen is so small that an excess is always furnished with the food, except, of course, in carefully planned experiments” (Folin).
We have seen at what low levels of proteid intake, nitrogen equilibrium can be established, and we may well have faith in the conception of an endogenous proteid katabolism which involves only minimal quantities of proteid. Further, we have observed the constant tendency of the body to maintain a condition of nitrogenous equilibrium, even with varying income, and how slow the body is to lay by nitrogen on a rich proteid diet, even when long deprived of proteid food; a fact difficult of explanation except on the assumption that the real need of the body for nitrogen is small, and that the tissues habitually carry a relatively large reserve of nitrogenous material. We may assume with Folin that “all the living protoplasm in the animal organism is suspended in a fluid very rich in proteid, and on account of the habitual use of more nitrogenous food than the tissues can use as proteid the organism is ordinarily in possession of approximately the maximum amount of reserved proteid in solution that it can advantageously retain. When the supply of food proteid is stopped, the excess of reserve proteid inside the organism is still sufficient to cause a rather large destruction of proteid during the first day or two of proteid starvation, and after that the proteid katabolism is very small, provided sufficient non-nitrogenous food is available. But even then, and for many days thereafter, the protoplasm of the tissues has still an abundant supply of dissolved proteid, and the normal activity of such tissues as the muscles is not at all impaired or diminished. When 30 grams or 40 grams of nitrogen have been lost by an average-sized man during a week or more of abstinence from nitrogenous food the living muscle tissues are still well supplied with all the proteid they can use. That this is so, is indicated on the one hand by the unchanged creatinin elimination, and on the other by the fact that one experiences no feeling of unusual fatigue or of inability to do one’s customary work. Because the organism at the end of such an experiment still has an abundance of available proteid in the nutritive fluids, it is at once seemingly wasteful with nitrogen when a return is made to nitrogenous food. This is why it only gradually, and only under the prolonged pressure of an excessive supply of food-proteid again acquires its original maximum store of this reserve material.”
We may reasonably suppose that the reserve of proteid present in the body is contained in the fluid media, and not as a part of the living protoplasm. Further, we are apparently justified in the belief that the sole form of proteid katabolism which is vitally important for the welfare of the body is the endogenous katabolism. This must be provided for adequately and indeed liberally, and in addition there should be sufficient intake to keep up an abundant supply of reserve proteid, but beyond these necessities there would seem to be no legitimate demand for additional proteid. The voluminous exogenous proteid katabolism so conspicuous in most individuals would seem to have no justification in fact, or in physiological reasoning. What good, for example, can be accomplished by this constant splitting off of nitrogen, with its subsequent speedy removal from the body? The organism can neither use it nor store it up, and why therefore should this daily burden of an excessive and accelerated proteid katabolism be borne? As we have seen, the energy of muscle work is derived mainly, and can come wholly, from the breaking down of non-nitrogenous materials, fats and carbohydrates. The very fact that an intake of say 120 grams of proteid is followed at once by the removal of the larger part of the contained nitrogen, as a result of the exogenous katabolism of the body, would seemingly warrant the view that the proteid so decomposed might advantageously be replaced by a corresponding amount of carbohydrate. In muscle work, as in heat production, carbohydrate and fat are the materials burned up, or oxidized. Proteid, on the other hand, is not so oxidized, at least not the nitrogen-containing portion of the molecule.
There are apparent only two possible reasons for assuming a need on the part of the body for the high exogenous katabolism of proteid so commonly observed. The one is that the carbonaceous residue left after the cleavage of nitrogen from the proteid molecule is better adapted for the needs of the body than either carbohydrate or fat. Although this does not seem very probable, it is of course a possibility and merits consideration. Feeding experiments, with a comparatively small proteid intake, continued over a sufficient length of time, would show conclusively how much weight should be attached to this hypothesis. The other possibility is that the body may derive some advantage from the presence, in the tissues and fluids, of the varied nitrogenous cleavage products split off from proteid so abundantly in exogenous katabolism. These substances are mainly amino-acids on their way to urea, and there is no apparent reason why they should be of service to the organism. Still, the processes going on in the tissues and organs of the body are intricate and not wholly understood, and we can conceive of some useful function of which as yet we have no knowledge. In the construction of tissue proteid, for example, as in a possible synthesis out of the fragments formed by hydrolytic cleavage, it is not impossible that certain corner-stones are needed, and that in order to obtain these there must be a more or less wasteful breaking down of food-proteid. However improbable this may seem, it, like the preceding hypothesis, can be tested in a way by adequate feeding experiments, which shall determine the effect on the body of a low proteid intake continued over a long period of time. On the other hand, it is equally plausible, and for some reasons more probable, to assume that this excessive exogenous katabolism may be in a measure prejudicial to the best interests of the body; that the many nitrogenous fragments formed in the efforts of the organism to prevent undue accumulation of reserve proteid may in the long run do as much harm as good.
Further, there is reason in the question whether the continual carrying of excessive amounts of nitrogen reserves in the shape of soluble proteid in the blood and lymph, and in the meshes of tissue and cell protoplasm, is advantageous for the maintenance of the highest degree of efficiency? We all recognize that an excessive accumulation of fat is distinctly disadvantageous to the welfare of the body, and there is, physiologically speaking, equally good ground for considering that the storage of unorganized proteid in amounts beyond all possible requirements of the body may be equally undesirable. Because less tangible to the eye, the accumulation of unnecessary proteid is not so easily recognizable, but this fact does not diminish the possible danger which such accumulation may constitute. It must be granted, however, that we are dealing here with hypotheses and not facts, but though hypothetical the suggestions made are of sufficient moment to merit attention and experimental study. In a later chapter, we shall have occasion to present some facts bearing on these questions.
In the meantime, we may lay due stress upon the significance of these views regarding proteid katabolism. We must accept as settled the general idea that there are two distinct forms of proteid katabolism within the body; one form representing the decay of tissue or cell protoplasm, small in amount, with its own particular decomposition products, and absolutely essential for the continuance of life. The other form, the so-called exogenous katabolism, runs a totally different course with distinctive side-products and end-products; it is variable in extent, in harmony with variations in proteid intake, and subject to the suspicion that at the level ordinarily maintained it constitutes a menace to the preservation of that high degree of efficiency which is an attribute of good health.