Amino Acids For Glutamine Synthesis

The branched-chain amino acids (BCAAs) are comprised of valine, leucine, and isoleucine. The BCAAs have been shown to have various functions such as serving as a nitrogen source for glutamine synthesis in skeletal muscle. In addition, they are the primary amino acids that are oxidized (used as fuel) in tissues other than the liver. Keep in mind, however, that all tissues can convert amino acids into Krebs cycle intermediates and vice versa This occurs via transamination reactions (e.g., alanine pyruvate, aspartate oxaloacetate, glutamate a-ketoglutarate). An abundance of animal and human studies have examined the potential utility of BCAA supplementation in various conditions (e.g., postsurgery, burns, starvation, carbohydrate depletion, exercise, etc.).

Animal Studies

In rats that were subjected to 15% full-thickness scald burns, regular TPN (21% BCAA) or BCAA-enriched TPN (45% BCAA) was administered for 48 hours after resuscitation by saline infusion for 24 hours. The solutions received by the two groups of rats were isocaloric (same number of calories) and isonitrogenous (same amount of amino acid-derived nitrogen). The BCAA-enriched TPN significantly improved liver and rectus abdominus muscle RNA and protein levels more than the conventional TPN. In rats with acute liver failure, the provision of BCAA improved whole-body protein synthesis in comparison to saline, glucose, or a standard amino acid formula Kawamura et al. compared amino acid solutions containing 25%, 30%, 40%, 45%, and 50% BCAAs on protein catabolism in rats that had been made septic via ligature and puncture of the cecum. They found that a solution of 45% BCAAs was most effective at influencing nitrogen balance.

On the other hand, many studies have shown no effect from BCAA administration. In rats give
TPN with either low (~20% BCAA) or high (~50% BCAA) concentrations of BCAA after surgery, they found no difference in nitrogen balance or in the rate of liver protein synthesis. Seventy-one burned guinea pigs were divided into six groups. 10%, 20%, 30% calories as whey protein with the remaining three groups having equivalent whey protein (10%, 20%, 30%) plus BCAA supplementation so as to increase the percentage of BCAAs to 50% of the total amino acids Interestingly, BCAA administration worsened cumulative nitrogen balance and mortality during the 14 days of administration. In protein-starved rats, the administration of BCAAs did not improve the healing of musculo-aponeurotic wounds of the abdominal wall.

Human Studies

In a large-scale study of 173 surgical patients with gastric cancer, the supplementation of TPN with BCAAs significantly improved nitrogen balance. BCAA-rich TPN improved the mortality rate in septic patients. Furthermore, BCAA administration has positive effects in normal individuals. The overnight infusion of BCAAs significantly reduced skeletal muscle breakdown in normal volunteers Also, the oral ingestion of BCAAs with an equal amount of essential amino acids (threonine, methionine, and histidine) was studied in normal men. Direct measure of skeletal muscle protein synthesis via tracer incorporation revealed no differences between groups. However, whole-body phenylalanine flux was reduced to a greater extent by the BCAAs, thus indicating a suppression of whole-body proteolysis.

Several studies show no effect of BCAA administration. TPN supplemented with BCAAs (44.6% BCAAs) did not affect nitrogen balance differently than standard TPN (19% BCAAs) in critically ill patients In patients that had undergone elective abdominal surgery, TPN was supplemented with either glutamine, OKG, or BCAAs. Both glutamine and OKG reduced the loss of intramuscular glutamine with the BCAAs having no such effect. In patients that were injured or septic, BCAA supplementation had no effect on nitrogen balance Thus, in the clinically ill population, the effects of BCAA are equivocal.

Several studies suggest an ergogenic effect of BCAA supplementation in exercising individuals. Sixteen subjects participating in a 21-day trek at an altitude of 3255 meters (10,679 feet) were age, sex, and fitness-matched in a double-blind, placebo-controlled study. They received a placebo or BCAAs . During the trek, the mean daily energy intake decreased by 4% in both groups compared to sea level. The BCAA and placebo groups lost 1. 7% and 2.8% body mass. Fat mass decreased in the BCAA (-11.7%) and placebo (-10.3%) groups moreover, lean body mass improved in the BCAA group (+1.5%) with no change in the placebo group. Lower limb maximal power decreased less in the BCAA than in the placebo (-2.4% versus 7.8%). Arm muscle cross-sectional area did not change in the BCAA group, on the other hand, the placebo group experienced a 6.8% decrease. Thus, BCAA supplementation has a slight anabolic effect, an anticatabolic effect, and lessens the drop in muscular power as a result of exercising in high altitudes .

Bigard et al. examined 24 highly trained subjects that participated in six consecutive sessions of ski mountaineering (6-8 hours per session, 2500-4100 meters altitude). Half of the subjects ingested BCAAs while the other half consumed a carbohydrate placebo. Further, each subject consumed a standard prepackaged diet that was isocaloric. Body weight decreased significantly in the placebo group (-2.1%); however, the weight loss in the BCAA group was not significant (-1.2%). Body composition alterations were not different between groups. Peak power measured during incremental bicycle exercise decreased in the placebo but not in the BCAA group. Maximal voluntary contraction (MVC) strength (isometric) of the knee extensors was not different between groups. In this study, BCAA administration had equivocal effects (i.e., less weight loss but no differences in body composition, maintained higher peak power output on the bicycle but no differences in MVC of the knee extensors). The reasons for these discrepancies are unclear.

Thirty days of oral consumption of 14 g/day of BCAAs (50% leucine, 25% valine and isoleucine each) resulted in a slight but significant increase (+ 1.3%) in fat-free mass and grip strength (+8.1%) in healthy untrained male subjects 89 It is not clear if the change in fat-free mass reflected an increase in skeletal muscle protein or other tissue protein. In a group of elite wrestlers, the effects of BCAA administration (0.9 g/kg/day) during caloric restriction was examined. Twenty-five wrestlers restricted caloric intake for 19 days using a hypocaloric control, hypo caloric high protein, hypocaloric low protein, or a hypo caloric high BCAA diet. Using magnetic resonance imaging technology, they found the BCAA group had the greatest body weight and fat loss of the treatment groups. Of particular interest is the fact that the BCAA­supplemented group experienced the greatest abdominal visceral fat loss (-34.4%). This would suggest a reduction in cardiovascular disease risk as a result of BCAA supplementation.

The effects of BCAA administration during a 30­kilometer cross-country race and a full marathon were examined by Blomstrand and Newsholme When BCAAs (7.5-12 g) were ingested during exercise, the plasma and skeletal muscle concentration of these amino acids increased, whereas the placebo group experienced a drop in BCAA concentration in plasma with no change in skeletal muscle. Moreover, the placebo group had a 20-40% increase in the muscle concentration of tyrosine and phenylalanine and an increased plasma concentration of these amino acids. The increased concentrations of phenylalanine and tyrosine would suggest a net protein degradation during exercise inasmuch as skeletal muscle does not take up or metabolize these two amino acids. But in subjects give
BCAAs, no such change in plasma phenylalanine or tyrosine was observed. Thus, BCAAs given during prolonged endurance events may have an antiproteolytic effect.

BCAAs may further reduce the protein breakdown associated with resistance-type exercises. Five men performed single-leg knee extensions for 60 minutes at 71 % of maximal work capacity with or without BCAA supplementation. Intramuscular BCAA concentrations were higher for the BCAA trial and remained higher throughout the exercise bout. Furthermore, the net release of essential amino acids from skeletal muscle was higher in the control than in the BCAA group, thus suggesting an attenuation of muscle protein breakdown during exercise.

On the contrary, Blomstrand et al. 93 found that the provision of BCAA with carbohydrates was no different than carbohydrates alone with regard to decreasing proteolysis during exercise, although BCAA ingestion may have a glycogen-sparing effect. In another study that investigated the effects of a 6-week endurance training program with daily BCAA 06, 2, and 2 g of leucine, isoleucine, and valine, respectively) supplementation, there were no differences (in comparison to the placebo) in the number of capillaries per fiber, muscle fiber composition, or muscle fiber cross-sectional area as a result of BCAA ingestion.

Although clinical evidence is weak, data from human exercise studies suggest a potential antiproteolytic effect of BCAA ingestion. Doses ranging from 6-14 g daily may be needed to inhibit protein breakdown.