This article [Hodges and Snyder, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15571244)] is really interesting and cites research showing that L-glutamine is the major energy source for cultured reticulocytes (immature red blood cells) and other cultured cell types and that glutamine + inosine (or other purines) can rescue cultured cells in media that lack glucose. In those articles, it's interesting that pyruvate or uridine or glutamate were not protective against glucose deprivation. In cultured lymphocytes or in lymphocytes in vivo (or in reticulocytes in vivo), as examples of cell types in which the activities of the de novo purine biosynthetic enzymes are very high, exogenous glutamine (i.e. adequate glutamine availability) would be important for de novo purine biosynthesis. But the main point of these articles and of all the articles showing protection against postischemic ATP and phosphocreatine depletion (the PCr depletion occurs in response to ATP depletion) in the heart and other tissues [Khogali et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9602431); Wischmeyer et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/14621120); Stottrup et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/17042921); (http://scholar.google.com/scholar?num=100&hl=en&lr=&cites=780779484133987619)] is that glutamine is being converted into tricarboxylic acid cycle (TCA) cycle substrates (i.e. entering the TCA cycle as 2-oxoglutarate or another TCA cycle intermediate) and acting as an anaplerotic substrate and "energy source." Many articles discuss the fact that glutamine is the major energy source for cells lining the upper intestine in the fasted state (the cells take up glutamine from the blood). Many articles show that exogenous glutamine improves glycogen and glutathione replenishment following ischemia or metabolic stress (even in the context of exercise, for example), including the ones by Stottrup et al. (2006) and Wischmeyer et al. (2004), respectively.
Everyone's afraid of increasing extracellular glutamate in the brain, but no one seems to consider the fact that the provision of exogenous glutamine could spare significant amounts of ATP (glutamine synthetase is ATP-consuming, and the consumption of ATP at single enzymatic steps begins to become very significant in the context of something like glutamine synthesis). The amounts of glutamine that are synthesized in different tissues are very large. Also, some articles make the erroneous statement that changes in the plasma glutamine concentration, which is, incidentally, drastically depleted following high-intensity exercise, occur independently of changes in the rate of efflux of glutamine or glutamate from the brain interstitial fluid (ISF). This is not true as a general statement but is probably true, under experimental conditions, in O'Kane et al. (1999) cite research showing that glutamate is exported across the luminal membranes of cerebral vascular endothelial cells in response to an intracellular glutamate concentration, in endothelial cells, that exceeds the plasma concentration of glutamate. Glutamate is known to be exported across the abluminal membrane (between the ISF and endothelial cell cytosol) into endothelial cells, glutamine is taken up into endothelial cells from the blood, and glutamate+glutamine efflux increases in response to ischemia or glucose deprivation or anoxia. That means that the plasma glutamate concentration, which is increased in response to exogenous glutamine, can determine the rate of efflux of glutamate from the CNS, at least under conditions that either increase glutamate efflux across the abluminal membranes of endothelial cells or decrease the plasma glutamate concentration (such as high-intensity exercise or muscle-wasting conditions, as in protein-energy malnutrition in chronic disease states). So under conditions of ischemia, maintaining the plasma glutamine concentration could, in my opinion, be expected to help, indirectly, to maintain the pools of TCA cycle intermediates in neurons and astrocytes (by limiting glutamine+glutamate efflux from the brain). The assumption seems to be that glutamine can only be converted into glutamate in cells or in the brain or that all of the glutamine is going to remain as extracellular glutamate. Glutamine is rapidly converted into aspartate and 2-oxoglutarate (alpha-ketoglutarate), etc., and most glutamate in the brain is intracellular. This article shows that exogenous alpha-ketoglutarate (the carbon skeleton of glutamine/glutamate and a TCA cycle intermediate) or pyruvate can be neuroprotective against PARP-activation-induced neuronal loss [Ying et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12142562)]. I have a lot of other articles on my computer that show the same thing in neurons (increases in or maintenance of ATP levels with combinations of exogenous glutamine or aspartate, along with purines, especially). A person would nonetheless want to talk to his or her doctor before using any supplement. But this is the type of thing that could help explain the exercise intolerance of people in chronic disease states or the neurotrophic effects that voluntary exercise can have, providing the depletions of plasma glutamine are not excessively prolonged.
I used to think, as others with an interest in sports nutrition have thought, that glutamate or alpha-ketoglutarate would be superior to glutamine for various purposes, given that glutamine produces more ammonia than glutamate or alpha-ketoglutarate do (alpha-ketoglutarate contains no nitrogen). In my opinion, based on various articles and arguments I've seen, this is probably not true. In one article I have, the author makes a convincing case that glutamine is superior, by virtue of its ability to "spare" glutamate that would otherwise be used for glutamine biosynthesis (an ATP-consuming process). That, besides the replenishment of TCA cycle intermediates, could account for some of the cell-energy-maintaining effects of exogenous glutamine.
The conversion of glutamine into aspartate or alpha-ketoglutarate (2-oxoglutarate) could also play a role in the supposed ATP-buffering effects of exogenous glutamine. Another "layer" to anaplerosis is that an excess of acetyl-CoA or acyl-CoA's can, by sequestering free CoA, inhibit the alpha-ketoglutarate dehydrogenase (KGDH) reaction, and true anaplerosis, under those conditions, requires that substrates enter the TCA cycle at a point that bypasses the "rate-limited" KGDH step (http://hardcorephysiologyfun.blogspot.com/2009/01/coenzyme-sequestration.html). The changes in the ratios of acetyl-CoA to free CoA or to acyl-CoA's, other than acetyl-CoA, that occur, in myocytes or other cell types, during exercise depend on the intensity and duration of the exercise. Another effect of the glutamine-induced increases in the aspartate pools is that aspartate can help maintain the purine nucleotide cycle in the skeletal muscles during exercise. That's part of the rationale, in my opinion, for thinking about purines in conjunction with glutamine, given that purines can be depleted, to varying degrees, during exercise, from the muscles (and also other tissues, such as the liver and probably, in my view, the brain). There's a "purine nucleotide cycle" for salvaging purines in the brain, too, but it's not clear that it's necessarily as closely connected to the TCA cycle as the purine nucleotide cycle in the skeletal muscle is. The assumption in some articles is that the increase in the uptake of ammonia into the brain, during exercise, is partially responsible for central fatigue. That may be true to some extent, but ammonia has also been shown to increase growth hormone release, for example. There might be some "beneficial" or trophic effects, even if a slight increase in ISF ammonia limits the duration of exercise or produces some fatigue or cell-energy stress in the short term. But my point was that, even with the extra ammonia that glutamine could conceivably provide, glutamine supplementation has been shown to reduce ammonia accumulation, under some conditions. Low doses of arginine (6 grams or less, sometimes 9) are also typically combined with glutamine, given that arginine can increase ammonia disposal in the liver and conceivably antagonize the glutamine-induced increases in plasma bicarbonate, etc.
Morris (2004) [Morris, 2004: (http://jn.nutrition.org/cgi/reprint/134/10/2743S) (http://www.ncbi.nlm.nih.gov/pubmed/15465778?dopt=Abstract)] noted that arginine biosynthesis consumes 2 moles of ATP per mole of citrulline, and this could suggest, in my opinion, that exogenous arginine would be preferable to citrulline. Exogenous glutamine can increase plasma citrulline, which is then converted into arginine in the kidneys. This is the main site at which blood-borne arginine is synthesized. It's not possible to overcome the requirement for renal arginine biosynthesis, though. When people compare arginine and citrulline, the "neutral" influence of citrulline on urea production (given that citrulline has one fewer amine groups than arginine does) is viewed as being advantageous. The argument of Morris (2004), namely that arginine formation consumes ATP, suggests, in my opinion, that arginine would be a better choice. It's true that arginine tends to be taken up by the liver en masse, but the elevations in plasma arginine, in response to exogenous arginine, require at least a couple of weeks, I think, or longer, to emerge. So the short-term elevations of plasma arginine, in response to citrulline, Even though ornithine might appear to be favorable in its capacity to "spare nitrogen," by reducing ammonia levels, and to not produce the dose-limiting side effects that arginine produces (in doses of arginine in excess of 9 g/dose or even 9 g/d), that argument (the idea that ammonia scavenging or less ureagenesis is the be-all and end-all of these types of approaches, to buffering plasma glutamine and TCA cycle intermediates in the skeletal muscles or brain or elsewhere) has carried too much sway and is not really valid, in my opinion, under normal conditions (i.e. in the absence of hyperammonemia, such as in the context of hepatic encephalopathy, induced by hepatic failure or renal failure, etc.). Additionally, ornithine can suppress creatine biosynthesis, but increases in plasma citrulline or arginine have the potential to increase creatine biosynthesis (see link below). That distinction, between arginine and ornithine, is likely, in my opinion, to be especially important in the context of in situ (it's both in situ and de novo) creatine biosynthesis in the brain [(http://hardcorephysiologyfun.blogspot.com/2009/02/glutamate-glutamine-cycle-de-novo.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-folate-cobalamin.html)].
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