Perhaps the most popular of the anticatabolic supplements, glutamine is the amide of the amino acid glutamate. Glutamine is synthesized from glutamate by the action of glutamine synthetase. Glutamate is formed from a-ketoglutarate, an intermediate of the Krebs cycle, and ammonia.
What is Glutamine?
Glutamine is the most abundant amino acid in plasma and skeletal muscle and accounts for greater than 60% of the total intramuscular free amino acid pool. Furthermore, skeletal muscle is quantitatively the most important site of glutamine synthesis even though glutamine synthetase activity is relatively low per unit mass in skeletal muscle. Adipose tissue may also represent a site of glutamine synthesis similar in magnitude to skeletal muscle.
In addition, the lungs, liver, and brain are other sites of glutamine synthesis.
Glutamine is one of the major fuels of the gut, particularly during fasting. In fact, the GI tract accounts for approximately 40% of the total glutamine that is used by the body. Glutamine metabolism in the GI tract is similar whether one has fasted or has recently consumed a meal.
The use of glutamine (and other amino acids) by the GI tract is partly due to high turnover of intestinal mucosal cells and the need for continual provision of amino acids to sustain high protein synthetic rates. The health of these cells is critical not only for normal uptake of nutrients, but also because these cells serve as a barrier or protection against invading bacteria from the lumen of the gut. Thus, cells of the GI tract may be preferentially supplied amino acids for oxidation and protein synthesis at the expense of skeletal muscle protein. We speculate that by providing extra exogenous glutamine (via dietary supplementation), you can spare intramuscular glutamine while feeding the GI tract. Thus, you would avoid muscle proteolysis secondary to lower concentrations of glutamine.
Besides the small intestine (i.e., enterocytes), cells of the immune system (i.e., neutrophils, thymocytes, lymphocytes, and macrophages) and hair follicles use glutamine as fuel. Glutamine is used for glucose and urea synthesis in the liver, whereas the brain uses glutamine as a precursor for neurotransmitter substances. In the normal fed state, and to an even greater extent during fasting and metabolic acidosis, glutamine is used as fuel by the kidneys (i.e., kidneys use glutamine to support renal ammoniagenesis) During metabolic acidosis, glutamine is converted to a-ketoglutarate, thus generating ammonium ions . The excretion of ammonium ions helps buffer the acidotic condition.
Evidence indicates that glutamine is important for the maintenance of skeletal muscle protein levels. The reclassification of glutamine as a conditionally essential amino acid is based on the notion that under certain stressful conditions, the body's need for glutamine exceeds its ability to synthesize glutamine endogenously. But with the provision of exogenous glutamine, the loss of skeletal muscle protein during stressful states may be alleviated.
Because skeletal muscle accounts for most of the protein pool in the body, the regulation of protein metabolism in skeletal muscle is important for whole-body protein homeostasis. Skeletal muscle and adipose tissue represent the most important source of glutamine However, skeletal muscle accounts for a much larger fraction of the body's total mass and is therefore more important than adipose tissue as a source of glutamine. According to Wagenmakers, the liver can oxidize most of the amino acids, whereas skeletal muscle can oxidize amino acids (i.e., the branched-chain amino acids, aspartate, asparagine, and glutamate). This is important for the oxidation of these amino acids and for the conversion of these amino acids into glutamine and alanine.
The effect of glutamine on protein synthesis and degradation in cultured rat skeletal muscle myotubes (developing skeletal muscle cell) under normal and heat-stressed conditions was assessed by Zhou and Thompson. They found that glutamine augments protein synthesis in myotubes that are under heat-stressed conditions; however, there was no effect on myotubes under normal conditions. A similar study from the University of Alberta found a positive relationship between intracellular concentrations of glutamine and the rate of muscle protein synthesis in isolated chick extensor digitorum communis muscle. That is, the greater the glutamine concentration, the greater the anabolic effect on these skeletal muscles.
The regulation of cellular volume is intimately associated with protein synthesis and degradation. An increase in cellular volume or hydration status acts as an anabolic signal, whereas a decrease in cellular volume promotes catabolic processes. Evidence suggests that glutamine may exert an anticatabolic effect by mediating increases in cellular volume. 20 Using an isolated rat skeletal muscle preparation, changes in the osmolarity of the surrounding medium affected the rates of glutamine and alanine release from skeletal muscle.
MacLennan found that increasing the concentration of glutamine significantly increased intracellular glutamine and protein synthesis in the absence of insulin in perfused rat skeletal muscle. Further, glutamine has an anticatabolic effect on the noncontractile protein constituent of rat skeletal muscle.
The depletion of intramuscular glutamine is associated with increased muscle catabolism. Thus, it is important that these stores are maintained to prevent the loss of muscle protein. The infusion of the dipeptide, alanyl-glutamine, can lessen muscle atrophy and glutamine synthetase production in rats given hydrocortisone 21-acetate (a type of glucocorticoid, a catabolic steroid with respect to skeletal muscle) 24 The mechanisms by which glutamine decreases glucocorticoid-induced muscle atrophy are not associated with changes in plasma levels of insulin-like growth factor 1 ClGF-1) or insulin-like growth factor binding proteins 25 Although at the molecular level, glutamine prevents the down-regulation of myosin-heavy chain synthesis that is seen in glucocorticoid-induced muscle atrophy.
In dogs that had undergone a laparotomy (an abdominal operation), the effects of a saline or an amino acid solution (with or without glutamine) on skeletal muscle nitrogen was determined before and 24 hours after surgery Skeletal muscle nitrogen declined in the placebotreated animals as well as those that received only 2 g/kg of an amino acid solution (with or without glutamine). However, both intracellular nitrogen and glutamine were maintained in animals that received 4 g/kg of solution regardless of whether glutamine was present. In this case, providing sufficient amino acid nutrition may preserve intramuscular glutamine levels and may be needed for preservation of muscle protein. Roth et al found that the infusion of the dipeptide alanylglu tamine reduced nitrogen release from the hindlimb of anesthetized postoperative dogs.
In septic rats, the rate of glutamine production in skeletal muscle is markedly elevated, although increasing the intramuscular concentrations of glutamine in septic rats did not alter muscle protein synthesis On the other hand, the infusion of an alanyl-glutamine dipeptide increased protein synthesis in liver and skeletal muscle of rats that were infected with Escherichia coli.
The effects of L-glutamine provision (20 g/kg) and swim training (3 hrs/day) on tumor growth in rats was examined by Shewchuk et al After 14 days of glutamine treatment, the average tumor weight of the glutaminetreated rats was less than in the untreated group. Exercise had no effect on tumor growth whether the animal received glutamine or not However, Austgen et al found that the provision of 20% of total parenteral nutrition (TPN) protein as glutamine had no effect on tumor growth in rats implanted with methylcholanthreneinduced fibrosarcoma.
Several clinical studies in humans have, for the most part, confirmed the effectiveness of glutamine in the prevention or lessening of muscle mass or protein during times of stress or illness. In a human study comparing the effects of glutamine versus glycine, investigators found that the enteral (direct feeding into the intestine) infusion of glutamine increased protein synthesis Conversely, an isonitrogenous amount of the amino acid glycine did not affect protein synthesis but did slightly decrease proteolysis. Thus, the mere provision of amino acid nitrogen does not produce the anticatabolic effects seen with glutamine.
Hammarqvist et al examined the role of glutamine as part of TPN in patients who had undergone elective abdominal surgery. TPN provides the caloric needs of patients via a catheter into the neck vein (subclavian vein). Patients received a conventional amino acid solution with or without glutamine. The glutamine group received 0.285 g/kg body weight per day. This is about 21 g of glutamine for a 75-kg individual. They found that the addition of glutamine to TPN improved nitrogen balance and lessened the decrease in protein synthesis. In patients who had undergone surgical removal of the gallbladder, the addition of an alanyl-glutamine dipeptide improved nitrogen balance and prevented a decline in muscle protein synthesis.
The use of another glutamine-containing dipeptide, glycyl-glutamine, preserved free glutamine levels in skeletal muscle after surgery; but when treatment was discontinued, skeletal muscle levels of free glutamine dropped in spite of normal enteral nutrition. However, in patients who had undergone heart surgery, the administration of large doses of glutamine did not prevent endotoxemia during or after surgery.
Perhaps another mechanism by which glutamine could exert anticatabolic effects is via an enhancement of plasma growth hormone concentration. Nine healthy subjects consumed 2 g of glutamine dissolved in a cola drink and investigators found an increase in plasma growth hormone 90 minutes postingestion. Whether chronic ingestion of glutamine results in a consistent daily increase is not known.
There is a scarcity of data regarding glutamine supplementation as a mode of altering body composition . Rosene et al examined the effects of 14 days of high-dose (0.35 g/kg body weight per day) glutamine supplementation in wrestlers consuming a hypocaloric diet. These investigators found that the glutamine group maintained positive nitrogen balance while the placebo group was in negative nitrogen balance after the 14-day treatment.
Safety and Toxicity
The high doses of glutamine that are needed for exerting an anticatabolic effect cannot be met via a normal diet. Thus, the safety of such high doses has often been questioned.
Anecdotal reports from bodybuilders who consume up to 40-50 g of glutamine per day without any ill effects suggest that glutamine is quite safe.
Work by Ziegler et al further confirm what many bodybuilders have believed from their personal experience. In an initial short-term study, oral doses of glutamine (0, 0.1, and 0.3 g/kg; 0.3 g/kg is equal to 22.5 g for a 75-kg individual) produced an acute rise in plasma glutamine as well as in amino acids known to be end products of glutamine metabolism (i.e. alanine, citrulline, arginine). However, toxicity was not evident as indicated by the lack of change in ammonia or glutamate levels. As a component of TPN (glutamine dose of 0.285 and 0.570 g/kg body weight per day), glutamine had no harmful effects after a period of 5 days of administration in normal subjects.
The safety of glutamine use was confirmed in patients receiving glutamine for several weeks Glutamine infusion as a dipeptide (glycyl-glutamine) was examined in poly trauma patients. Using doses equal to 14,21, and 28 g of glutamine (calculated for a 70-kg individual) per day, they found no ill effects of glycyl-glutamine.
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