The strict division of amino acids into categories of essentiality (nondispensability) and nonessentiality (dispensability) is now recognized as being too crude to be useful in attempting to understand completely the ways in which amino acids are metabolized in health and disease. No amino acid fulfills the new criterion of being “conditionally essential” better than glutamine.
Glutamine is involved in a large variety of metabolic processes as a precursor (e.g., for nucleobases); as a component of acid-base homeostasis; in regulation of cell volume as a regulator of the balance between anabolism and catabolism of fat, carbohydrate, and protein; as a fuel for the gut and cells of the immune system; and of course as a component of protein. Over the past 15 years it has become apparent that there are many situations in which the input to the free pool of glutamine (i.e., from the diet, from protein breakdown, and by depletion of the intracellular stores in muscle) are not always able to satisfy the requirements for glutamine. In such circumstances glutamine is a conditionally essential amino acid without which the body operates suboptimally.
There are now a number of well-defined circumstances in which delivery of exogenous glutamine is able to confer benefit upon patients whose requirement has increased. Examples of these are presented. We still do not fully understand the mechanisms by which glutamine confers its beneficial effects in all cases. A number of major puzzles remain, e.g., why glutamine appears to be conditionally essential when there is rarely a fall in blood glutamine in circumstances where benefit can be shown after supplementation. To what extent the lessons we have learned from clinical situations can be applied in physically active subjects is not yet known.
Exercise and Amino Acid Metabolism
The controversy regarding the extent to which protein is used as a fuel is a very old one. Strong evidence now indicates that as long as energy requirements are met, given a diet of normal composition, high rates of physical activity will not predicate the greater requirement for protein. Although some argue that in order to maximize protein accretion or adaptation of muscle architecture (e.g., to increase mitochondrial capacity) consumption of dietary protein at high rates is beneficial, the evidence for this position is not strong.
If there is no general need for extra protein, does physical activity confer an extra requirement for glutamine? If so, can glutamine be used as a protective agent (i.e., preventing damage) and also as what might be called a rescue agent, i.e., in speeding recovery from damage associated with exercise?
Although a number of tantalizing possibilities exist, the evidence is rather sparse. For the hypothesis that regular, vigorous physical exercise causes increased glutamine requirements to be true. exercise would have to cause a fall in glutamine stores or, at least, institute circumstances in which glutamine supplementation were beneficial, even if no fall in glutamine were observed.
Exercise at very high rates certainly depletes glutamate in skeletal muscle and (according to animal studies), if oxygen delivery is compromised, also in the heart. Normally glutamine concentrations in these tissues are sufficiently high such that measuring any diminution in glutamine pool size in muscle during exercise is rather difficult; certainly if glutamine fell below some critical level at which its ability to supply metabolic processes in muscle or elsewhere were compromised then supplementation with glutamine might make sense. For example, there is good evidence that the ability to work at near maximal rates of oxygen consumption is limited by the constant draining of citric acid cycle intermediates, e.g., escape of succinate and malate. Glutamate is an obvious precursor for 2oxoglutarate which could top up the citric acid cycle intermediates, but glutamate concentrations themselves can fall dramatically in strenuous exercise, suggesting that the glutamate pool size is insufficient. Glutamine is able to be converted to glutamate, very efficiently by phosphate-dependent glutaminase which is present in skeletal muscle and heart mitochondria, and as long as glutamine can get into them it should act as a precursor of 2-oxoglutarate. The problem is, if this is so why does muscle glutamine concentration not show a bigger fall? Furthermore, would additional glutamine (i.e., an amount over and above the residual store) have any benefit? These are ideas that need to be tested.
The ability to mount defenses against metabolic acidosis very much depends upon glutamine availability. To what extent this is important during physical exercise is not known.
Exercise is also said to be associated with an increase in free-radical induced damage, and there is good evidence that, paradoxically, glutamine may be a better precursor of intracellular glutamate for the synthesis of glutathione (e.g., in white cells and liver) than extracellular glutamate. Under such circumstances glutamine availability may help maintain the cellular defenses against oxidative damage.
There is a substantial amount of anecdotal evidence that highly trained subjects are more susceptible to infection, in particular upper respiratory tract infection. Whether this is because of a weakening of epithelial barriers against micro-organisms or because of an inability of the immune system to cope adequately is not known, but there is certainly a wealth of evidence to suggest that cells of the immune system are better able to cope when they are well supplied with glutamine. Evidence is emerging that glutamine may afford some benefit when given after a substantial bout of exercise, e.g., after a marathon or half marathon, but it is not known to what extent glutamine provision before exercise can act as a protective agent.
Glutamine is said to improve mood in some circumstances, but no very good data exist in healthy individuals.
It seems likely that glutamine itself is the missing magic ingredient in many cases, but a number of enthusiasts have espoused glutamate and 2-oxoglutarate, either on its own as the Na salt or as the ornithine or aspartate salts, but the benefit of such supplements has not been proven.
Other amino acids that have been thought to be conditionally essential under certain circumstances and that might be considered with respect to physical exercise are arginine, histidine, and cysteine. The arginine/nitric oxide story is well known, but I have been unable to discover any evidence of a beneficial effect of arginine with respect to physical activity. Histidine is said to have a role in mopping up free radicals, and cysteine may well contribute toward glutathione synthesis. However, the difficulties of delivering sulphur-containing amino acids as supplements are well known, and it seems unlikely that it would be possible to produce such supplements in a stable and palatable form.
Functional Foods and Oral Glutamine
It is still not known to what extent glutamine-containing proteins are broken down to free glutamine and then absorbed or whether absorption occurs as glutamine-containing peptides; nor is it known to what extent protein-bound glutamine appears as free glutamine in the hepatic portal vein or whether glutamine is largely metabolized by the cells of the gastrointestinal tract Nevertheless, a number of companies are working on so-called functional foods, which contain large amounts of protein-bound glutamine, principally from wheat and milk proteins. These may be more effective ways of delivering glutamine to the body. Glutamine can be given effectively in substantial doses, e.g. up to 8 g/330 mL in water and despite a substantial (probably unwarranted) amount of worry about glutamine degradation and toxicity of the product 5-oxoproline, it seems that packaging glutamine in sachets for mixing with soft drinks, yogurt or milk based drinks is perfectly feasible way of supplementing dietary intake.
Future Research Needs
More research is needed to determine the way in which glutamine is handled by the gut, the specific requirements of particular metabolic processes for glutamine, and whether glutamine compartmentation limits the free exchange of the amino acid between different pools in the body. Better evidence is needed for the way in which glutamine has its beneficial effects in anabolism, the immune system, and in possibly combating free radical damage. Population groups that might benefit particularly, e.g., elite athletes and the elderly, need to be identified. Better information is also needed about the dose-response relationship between glutamine and its possible beneficial effects and also the possible downsides of giving large amounts of nonessential amino acids with an otherwise normal diet.
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