NW Spine - Library
Glutamine: A Multi-Functional Marvel
By Greg Bradley-Popovich, DPT, MSEP, MS, CSCS
© 2000
Originally published in Muscle Mag International (Portuguese version)
Some amino acids are rather simple in their purpose. For example, they may primarily serve to be linked to other amino acids during the formation of proteins. However, this description of simplicity does not begin to describe the amino acid glutamine. In addition to representing 3-4% of the amino acids found in common proteins (Rucker & Kosonen, 2000), glutamine is independently multifunctional, performing numerous physiological duties. When you appreciate the many roles of glutamine, it's really quite amazing all the responsibilities it assumes.
Glutamine Basics
Muscle tissue serves as a reservoir for the majority of the body's free amino acids. In fact, 80 percent of the free amino acids in the body are found within muscle cells. Of that 80 percent, 60 percent of this amino acid "pool" is comprised of glutamine. Thus, glutamine is the most common amino acid in blood and skeletal muscle (Antonio & Street, 1998). Of all the glutamine in the body, 95% of it is found inside cells such as muscle cells (Stipanuk & Watford, 2000).
Not only is glutamine versatile, it is also dynamic. For example, in rats it has been estimated that if glutamine synthesis were to cease, then all glutamine would be exhausted within seven hours. Amazingly, the amount of glutamine formed each day (50 to 120 grams) can exceed the amount found in the glutamine pool by many times. Glutamine can be synthesized at a rate faster than that of any other amino acid (Di Pasquale, 1997).
Glutamine is primarily synthesized in skeletal muscle, but some authors think that fat tissue may contribute equally. Really, skeletal muscle is not terribly good at making glutamine, but muscle comprises so much of our body weight that its production adds up (Antonio & Street, 1998). It is well known that in addition to making its own glutamine, muscle can take up glutamine from the circulation (Stipanuk & Watford, 2000). Other sites of glutamine synthesis included the lungs, the liver, and the brain. You can think of these sites as glutamine producers.
Still, other organs, tissues, and cells are primarily glutamine consumers. These glutamine swine include primarily the intestines and immune system cells, though hair follicles require glutamine as well. In fact, the gastrointestinal system utilizes 40% of the total glutamine produced in the body (Antonio & Street, 1998). This is due to the fact that the lining of the intestines replaces itself every three days and depends upon glutamine for both energy and synthesis of proteins and DNA (Kujath & Dhar, 1999).
Because glutamine can be synthesized by the human body, it was historically referred to as a nonessential amino acid meaning that dietary consumption was not necessary to maintain optimal glutamine levels. However, contemporary nutritionists often categorize glutamine as a conditionally essential amino acid meaning that at times the body's need for glutamine exceeds the body's production of glutamine. Glutamine is found in the typical diet, particularly in high calorie foods such as almonds, soybeans, and peanuts (Di Pasquale, 1997).
Several stressors can result in a decrease of muscle glutamine levels. These stressors include, but are not limited to, burns, fasting, malnutrition, uncontrolled diabetes, infections, trauma, surgery, and intense exercise. Indeed, stress can result in a reduction of glutamine stores up to 50 percent (Di Pasquale, 1997).
In general, glutamine is the first amino acid to be compromised and the last one to be replaced. Intramuscular glutamine is sacrificed in order to preserve immune and organ function. The body does up-regulate the production of glutamine during times of stress, but in many cases the supply cannot keep pace with the demand. Besides depleting glutamine, other amino acids such as the branch chain amino acids are also compromised because they are used to replace glutamine through a series of enzymatic reactions. This, in turn, results in fewer amino acids for construction of skeletal muscle contractile proteins (Di Pasquale, 1997).
Glutamine in Anabolism
One of glutamine's most important roles is to regulate protein synthesis. It fulfills this role by increasing protein synthesis while decreasing protein break down. In fact, the greater the amount of intramuscular glutamine, the greater is the rate of protein synthesis in muscle (Di Pasquale, 1997).
The effect of glutamine in a hospital setting is well known. In a variety of patients, glutamine improves nitrogen balance (a marker of increased protein synthesis) and immune function (Di Pasquale, 1997). Some authors suggest that the reason it is clinically superior to consume food through the digestive system as opposed to intravenous feeding in a hospital setting is because intravenous food preparations do not contain glutamine (Kujath & Dhar, 1999).
Glutamine may exert its anabolic role through a process known as cell volumizing, a term commonly used in discussions of creatine but which was originally used to describe the effects of a glutamine product. Certain amino acids, including glutamine, attract water and draw water into cells. Wherever glutamine goes, water follows. Research suggests that the more water that is found within a cell, the more anabolic the cell is, yet we still do not understand fully why this is the case. As you may have guessed, when cells begin losing water catabolic processes are favored over anabolic processes.
When compared to other amino acids, glutamine has considerable hydrating effects, which defends its importance in anabolism because a well-hydrated cell is an anabolic cell. Take for example livers cells. Research has shown that liver cells increase in volume by up to 12% following two minutes of glutamine exposure. Furthermore, the increased volume persists as long as the glutamine is still present. As glutamine is lost and the glutamine levels return to normal, water exits the muscle and catabolic processes ensue. So, too little glutamine may decrease muscle size in two ways. First, it may decrease the amount of protein found in muscle. Second, it may decrease muscular fullness and pumpability due to decreased fluid content in the muscle.
Glutamine in Anti-catabolism
As mentioned above, branch chain amino acids may be used to form glutamine during times of glutamine depletion. Traditionally, we may have assumed that high levels of branch chain amino acids were important because they directly exerted some effect in muscle cells. But interestingly, branch chain amino acids may provide an anti-catabolic action by maintaining glutamine levels. When branch chain amino acids are broken down, it is mainly for the purpose of forming glutamine (Di Pasquale, 1997). So, branch chain amino acids may be lower on the totem pole than glutamine according to your body's perception of importance.
Without the provision of supplemental glutamine, high levels of cortisol-like drugs result in muscle atrophy. Perhaps surprisingly, supplemental glutamine was shown in one study to prevent the normal loss of ribosomes (which manufacture protein) that occurs during treatment with cortisol-like drugs (Di Pasquale, 1997). The advantage of this finding is obvious. Glutamine has the potential to maintain an anabolic state by keeping the protein synthetic machinery intact and keeping the level of intramuscular amino acids uncompromised. Glutamine is therefore a powerful anti-catabolic that has obvious applications for those individuals who train with high intensity or who are at or near the point of over training, not to mention those who may be taking large amounts of cortisol-like drugs for medical purposes. Such anti-catabolic effects allow for the maintenance of your hard-earned muscle even in the most unfavorable metabolic situations.
Glutamine in Immunity
Both major glutamine consumers, the immune system and intestines, mainly utilize glutamine for synthesis of DNA and RNA and for energy production whereby glutamine's carbon skeleton enters an aerobic pathway known as the Krebs cycle. You may wonder what it is that the immune system and the gastrointestinal system have in common. Both systems are integral to preventing infection, but by two totally different mechanisms. For example, immune cells such as macrophages and lymphocytes attack foreign invaders such as bacteria. On the other hand, the cells of the gastrointestinal system form tight junctions that create a barrier to prevent infection of the body by potential unwelcome invaders ingested in the diet (Kujath & Dhar, 1999).
Some authors speculate that, during times of stress, glutamine consumption by the gastrointestinal system decreases glucose utilization by enterocytes in order to make more glucose available to other tissues that may need glucose more badly (Kujath & Dhar, 1999). Therefore, glutamine enhances immune function through both active (e.g., immune system cells) and passive mechanisms (e.g., gastrointestinal barrier).
It is well-known that physical trauma suppresses the immune system response. It is possible that this may be attributable to insufficient dietary intake or insufficient production of glutamine. Glutamine is necessary for lymphocyte proliferation, interleukin (a substance important in immunity) production, antibody synthesis, and macrophage phagocytosis (consumption of foreign invaders) (Gotovtseva, Surkina, & Uchakin, 1998). Because muscular activity can affect the amount of glutamine produced and released from skeletal muscle, exercise can be thought of as potentially having a profound effect on immune function (Gotovtseva, Surkina, & Uchakin, 1998).
Glutamine in Overtraining
The concept of glutamine supplementation in exercising persons originates from the idea that exercise itself is a stressor, and most of the theoretical foundation for glutamine supplementation for athletes has been collected in just the past decade (Antonio & Street, 1998). Along these lines, intense isometric exercise has been shown to cause glutamine release from the muscles. Furthermore, prolonged aerobic activity is known to significantly decrease glutamine reserves. Extended periods of intense physical activity are known to suppress the immune system, and this may occur because of glutamine depletion. Also, high levels of catabolic hormones such as cortisol, which characterizes over training, or the synthetic equivalent, have been demonstrated to increase glutamine release from skeletal muscle while increasing consumption of glutamine in other cells such as those of the intestines and of the immune system (Di Pasquale, 1997).
One experiment examining the effects of over training on glutamine levels required four people to exercise two times per day for ten days. Blood levels of glutamine decreased in four of the participants within just six days of the protocol. After ten days, all five subjects demonstrated significantly decreased glutamine levels. Even after six days of rest, blood glutamine levels had still not returned to normal in two of the subjects (Antonio & Street, 1998).
Besides its anti-catabolic and immune enhancing functions, another avenue by which glutamine may assist in the preventative treatment of over training syndrome is by its role in fighting oxidation and the formation of free radicals. After it is converted to glutamic acid, glutamine is indirectly an antioxidant because it is a precursor to the powerful antioxidant tri-peptide glutathione (Di Pasquale, 1997). Obviously, free radical formation is increased during increased the same periods of intense exercise that may contribute to over training syndrome.
The relationship between low glutamine levels and over training is so strong that some researchers believe that monitoring glutamine levels is the best method to evaluate over training status, preferable even to monitoring testosterone and cortisol concentrations (Rowbottom, Keast, & Morton, 1998).
Other Roles of Glutamine
As if the many functions of glutamine previously described were not enough, glutamine has even been shown to play a role in fatty acid and glycogen metabolism. Greater availability of glutamine has been shown to enhance glycogen synthesis and storage and muscles. Glutamine is one of only six amino acids that can be used for energy in skeletal muscle cells (Antonio & Street, 1998), and it provides almost as much energy as an equivalent amount of sugar (Kujath & Dhar, 1999).
Glutamine's interaction with hormones is interesting as well. Just two grams of glutamine taken orally has been shown to significantly elevate growth hormone levels, although we are not certain how this occurred. Glutamine also increases secretion of gonadotropin releasing hormone, which is the hormone that causes the release of other hormones such as testosterone (Di Pasquale, 1997). Researchers have shown that oral glutamine supplementation decreases the concentration of fatty acids in the bloodstream (Di Pasquale, 1997). In mice consuming a high-fat diet, glutamine supplementation led to a decrease in body weight, blood sugar, and insulin levels (Antonio & Street, 1998).
In addition to the actions of glutamine discussed above, glutamine is important for blood clot formation where it acts to stabilize the clot (Hamilton & Gropper, 1987). In the brain, glutamine serves to transport toxic ammonia away from the brain, freely diffusing across the blood-brain barrier (Hamilton & Gropper, 1987). Furthermore, glutamine in the brain can be converted by enzymatic action to another amino acid called glutamic acid, which itself if an excitatory chemical, or which may be further altered to form GABA, an inhibitory chemical. Glutamine is involved in acid-base balance in which the kidney uses glutamine in a process to excrete acid (Stipanuk & Watford, 2000). Finally, glutamine donates a nitrogen atom to form substances such as glucosamine, a substance important for normal joint function (Stipanuk & Watford, 2000).
Stress: A Prerequisite for Glutamine Supplementation
One warning for those considering supplementing with glutamine: if you think that you can sit around and benefit from glutamine supplementation, then you're mistaken. It appears that glutamine supplementation is most beneficial when the body is under some degree of physical stress. For example, glutamine has been shown to act as an anti-catabolic in embryonic muscle cells under stress, but not in normal embryonic muscle cells (Antonio & Street, 1998). The same scenario is likely to hold true for the role of glutamine in immune function. In other words, glutamine supplementation bolsters the immune system best when there is an overwhelming degree of stress that would challenge the body's ability to manufacture enough glutamine.
Glutamine Delivery
At this point, you may be thinking that there is a sound rationale for glutamine supplementation in athletes such as bodybuilders. There exists, however, a problem of immense proportions when it comes to the practical applications of oral glutamine consumption. You'll recall that the enterocytes, or those cells lining the intestines, hungrily monopolize glutamine that is consumed in the diet. Enterocytes even steal glutamine from muscles out of the bloodstream to feed their need for energy (Stevens, 2000). The result of this voracious appetite by the enterocytes is that the majority of glutamine consumed orally does not make it past these cells. It has been estimated that up to two-thirds of oral glutamine supplement are metabolized by the enterocytes (Di Pasquale, 1997). This situation is sometimes referred to as the "glutamine paradox." Let's explore some options to address this problem.
One strategy to beat the enterocytes is to drown the enterocytes with large doses of glutamine in an attempt to satisfy the enterocytes while overwhelming them with sufficient glutamine so that a meaningful amount of glutamine finds its way into the bloodstream. However, this approach is neither practical nor cost-effective. Simply put, it is a waste of resources.
A better alternative is to seek a means of sneaking glutamine into the bloodstream not by going through enterocytes but rather by going around them. A possible method of avoiding the problem of hungry enterocytes may lie in a substance known as lysophosphatidylcholine, a lipid (fatty) substance that inserts itself into cell membranes. In general, lysophospholipids have a reputation for being great at dissolving a variety of substances in water because one end of the molecule is attracted to water and the other end is lipid soluble (Small, 2000).
Lysophosphatidylcholine, a kind of lysophospholipid, has been shown in studies to enhance absorption of substances through several kinds of cells in test tubes, and its inclusion in nasal sprays has shown an increase in drug absorption through the lining of the nasal passages. After incorporation into the cell membrane, lysophosphatidylcholine may temporarily destabilize cell membranes in enterocytes so that greater quantities of glutamine can be swept into the bloodstream. This is accomplished as lysophosphatidylcholine increases the porosity of cell membranes by helping channels to form that allows the transport of materials into cells. Thus, lysophosphatidylcholine increases the permeability of cell membranes, which causes an influx of substances surrounding the cells and a subsequent expansion of cells. Furthermore, through these very same mechanisms of increased permeability, glutamine may be absorbed upstream in the stomach. Absorption in the stomach would totally bypass the issue of enterocytes consuming the bulk of oral glutamine supplementation. Nevertheless, some nutritional biochemists have likened oral consumption of lysophosphatidylcholine to drinking Liquid Plumber. Until more research is conducted on the long-term gastrointestinal effects of lysophosphatidylcholine consumption, this author does not recommend consuming any supplement containing this compound.
You may want to be suspicious of any liquid glutamine supplements on the market because in this environment the glutamine spontaneously breaks down to form glutamic acid and the waste product ammonia. Such decomposition is most likely problematic only if the solution is over a month old (Kujath & Dhar, 1999).
Glutamine Dose
Now that you understand the glutamine paradox, you may wonder exactly how much glutamine you need to take to benefit from glutamine supplementation. Many medical studies involving severe circumstances indicate that 20 to 40 grams of glutamine achieves the best results (Di Pasquale, 1997). To increase nitrogen balance (a measure of protein synthesis) from 14 to 42 grams of glutamine have been used daily (Antonio & Street, 1998). Nevertheless, respected sports nutritionists suggest that athletes do not require as much glutamine supplementation as to severely ill hospital patients (Antonio & Street, 1998).
Although glutamine has been shown to be safe at relatively high levels of consumption over several days or weeks (Antonio & street, 1998), too much of a good thing is not a good thing. Very high levels of blood glutamine stimulate the liver to remove glutamine from the circulation (Di Pasquale, 1997) in order to possibly make glucose from the glutamine. One study showed that increasing the blood concentration of glutamine by three times resulted in a sevenfold increase in glucose formation from glutamine (Antonio & Street, 1998) How wasteful! Because glucose is readily available in the diet, we need not squander our precious glutamine by converting it to sugar. Furthermore, high levels of glutamine also cause the body to decrease its manufacture of glutamine.
Summary
Glutamine supplementation may be important for several kinds of athletes because of its ability to combat the effects of over training and to support the immune system. Strength trained athletes in particular may benefit from glutamine's ability to exert anabolic and anti-catabolic effects on muscle tissue. Indeed, if you’re serious about bodybuilding, glutamine may be your best friend because it keeps you healthy and helps you get the most out of your training efforts, especially when training intensely. But, science has yet to determine the clinical efficacy of glutamine supplementation for athletes to evaluate if its effects will be as impressive as its theoretical underpinnings.
About the Author
Dr. Greg Bradley-Popovich holds dual master's degrees in Exercise Physiology and Human Nutrition from West Virginia University as well as a doctorate in Physical Therapy from Creighton University. He is the Director of Clinical Research at Northwest Spine Management, Rehabilitation and Sports Conditioning in Portland, Oregon.
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