Monographs


BCAA

Nutritional therapy

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The three branched chain amino acids, L-Leucine, L-Isoleucine and L-Valine, are commonly known by their English abbreviation: BCAA (Branched Chain Amino Acids). These are essential amino acids that particularly play an important role in protein, energy and stress metabolism. They are important for a number of vital tissues and organs, including the immune system, the central and peripheral nervous system and the muscular tissue.

To delay or to reduce neurological symptoms in certain disorders, these amino acids are used therapeutically in catabolic situations (for example, serious infections, surgery, burns) and in syndromes such as phenylketonuria (PKU), hepatic encephalopathy, bipolar disorder, tardive dyskinesia and other neurological disorders. In healthy people, BCAAs are used to improve mental and physical performance, such as in athletes [1].

BCAAs are essential amino acids; the body is unable to produce these compounds itself. In principle, the body is able to form leucine, isoleucine and valine from their alpha-keto analogues, but these substances are usually not present in the diet, meaning people are dependent on supply through the food. Dietary protein contains a substantial percentage of BCAAs (approx. 15 - 20% of the amino acids in animal proteins). BCAAs account for approx. 35% of the need for essential amino acids.

In branched chain amino acids, as the name suggests, the side-chains are branched. Because of this unusual three-dimensional structure, the three amino acids fulfil a very individual role in metabolism. This means that, unlike the other amino acids, BCAAs do not have to be ‘processed’ in the liver first of all, but they enter the circulation immediately, meaning after a meal, the plasma concentrations are able to rise rapidly and significantly [2].

Because of their branching, BCAAs can also be particularly well integrated into muscular tissue. Almost 30% of all amino acids that are used for the synthesis of myofibrils (muscle fibres), are branched amino acids. The muscular tissue accounts for almost 40% of the total body weight. Therefore, many BCAAs are stored in the muscle proteins, but only a small percentage of those (0.01%) are available as free amino acids [3]. Furthermore, this trio is also very important in connective tissue structures.

Anabolic effect on muscle metabolism
BCAA supplementation shortly before and immediately after exercise has an anabolic effect on the muscle metabolism. This is because the speed of protein synthesis is increased and the speed of protein degradation is inhibited. Research in the surgical and orthopaedic fields has shown that appropriate intake of these amino acids boosts the development of the muscle cross-sectional area and muscle mass.
Following power training, the intake of several grams of BCAA can have a positive effect on the metabolism in the muscle cell nuclei (RNA-polymerase = ribonucleic acid)to such a degree that this results in a larger muscle cross-sectional area and amount of synthesised proteins, which also results in increased strength.

Recent research has revealed that especially a metabolite of leucine (ketoleucine) has a significant regulating effect on the protein metabolism. Leucine acts as a sort of spark that, in conjunction with insulin, incites protein synthesis [4-6]. For that reason, some researchers claim that is better to only supplement leucine, instead of all three of the BCAAs [7]. However, although isoleucine and valine are not able to initiate the protein synthesis themselves, they do provide the building blocks that are required once the anabolic processes have started. The BCAAs also have a significant synergetic effect on one another [6].

Energy production in times of stress
BCAAs are amino acids which are able to undergo glycolysis, that can very easily be converted into energy. If in times of psychological and/or physical stress there is a carbohydrate deficiency, the BCAAs act as a significant source of energy for skeletal muscle tissue. This is clearly an emergency solution, as in this method of energy provision the body’s own proteins (both from muscle tissue and immune protein) are used. At a later stage, the protein structures that are used for obtaining energy are rebuilt. Even so, it is a worthwhile emergency solution. For example, in endurance sports (e.g. cycle racing) up to 15% of the total energy that is used originates from the breakdown of body proteins [8]. In addition to the breakdown of muscle tissue, that also results in significant immune impairment. People who participate in endurance sports therefore have to ensure that they receive sufficient BCAAs in order to fulfil not only the usual need but also the additional amount that is consumed during a training session. BCAA supplementation before and after a training session should avoid muscle tissue being broken down to provide energy. Afterwards, it helps in the regeneration of muscle tissue that has been used.
In times of stress, an (additional) glutamine deficiency can result in higher consumption of BCAAs, because glutamine can be made from these three amino acids. A glutamine deficiency (for example, in intestinal problems) and a complete deficiency of the branched amino acids will unavoidably result in a loss of muscle mass and immunoglobulins. Supplementation with BCAAs reduces the rate at which other amino acids are broken down and used.

Brain function
BCAAs play various roles in the biochemistry of the brain.
Of course, as building blocks of proteins, as well as of energy, but also in the metabolism of glutamate, an exciting neurotransmitter. However, the most important way in which BCAAs have an effect on brain functions concerns the influence of the transport of the aromatic amino acids through the blood-brain barrier, which influences the availability of precursors for neurotransmitters [9].
BCAAs are transported through the blood-brain barrier to the brain (and other parts of the central nervous system) by means of an active transport mechanism. This transport mechanism is already saturated at normal plasma concentrations and the BCAAs share it with the aromatic amino acids (tryptophan, tyrosine and phenylalanine). Because BCAAs are usually present in large numbers, BCAAs usually win the competition for this transport system. When the concentration of BCAAs in the blood rises, which can happen in various normal and abnormal situations, that inhibits the absorption of aromatic amino acids in the brain, especially of tryptophan [1].

As a response to the decreased availability of the precursors, the production and release of the monoamine neurotransmitters serotonin, dopamine and noradrenaline that are produced from the aromatic amino acids, are reduced immediately and rapidly. This has consequences on (among others) the hormonal system, blood pressure and mood [1,10].

Conversely, if the concentration of BCAAs in the blood becomes (too) low, more aromatic amino acids are absorbed into the brain. If this happens to too great an extent, this can potentially result in the brain containing aromatic amino acid levels that are too high. This surplus can be converted into so-called fake hormones, or false neurotransmitters [11]. These are substances that can be responsible for serious psychological problems and even psychiatric disorders such as body dysmorphic disorders and schizophrenia. The latter syndrome is also one of the serious consequences of liver cirrhosis and hepato-encephalopathy [12].

Immune system
BCAAs are absolutely essential for the correct functioning of the immune system. Deficiencies in BCAAs inhibit various aspects of the immune system, including the activity of Natural Killer Cells and the proliferation of lymphocytes. Particularly lymphocytes use many BCAAs. In addition, BCAAs are building substances of the flexible side of the immunoglobulins; substances that form the humoral part of the immune system.
However, much is still unclear about how BCAAs act on the immune function. Most probable is that the main role of BCAAs for the immune system is the synthesis of proteins (antigen-performing proteins, immunoglobulins, cytokines, receptors, acute-phase proteins etc.) [13]. Additionally, a degree of the effect can be explained by a saving effect on L-glutamine.

Insulin production
In addition, BCAAs regulate the production of insulin, which again supports the absorption of amino acids into muscle tissue and delays the breakdown of muscle tissue. Additionally, leucine favourably intervenes in the mechanism of action of insulin and the use of glucose by muscle tissue. However, much is still unknown about the exact mechanisms [5].

Indications

In principle, BCAAs can render services in all stressful situations where muscle tissue is broken down, such as in serious infections, surgery, burns, calorie restriction and heavy physical exercise such as endurance sport.
In such situations, a deficiency in BCAAs occurs in the muscle tissue, as a result of which muscle weakness and fatigue can occur. BCAA supplementation then helps to remedy this deficiency, thus reducing the symptoms.
It is evident that people who suffer from stress have increased susceptibility to inflammations of tissues and organs that form part of the immune system in the mucous membranes (Common Mucosal Immune System).
 
The most important organs of this system are the intestine, the respiratory organs, throat, nose and oral cavities and the skin. Colds, chronic pharyngitis, colitis and also chronic feelings of fatigue are a few of the symptoms and disorders that can then arise.

A number of indications are explained below:
  • Sports: people who participate in ensurance sports use BCAAs to counteract the breakdown of muscle tissue for energy production. Also,through BCAA depletion, more tryptophan is absorbed into the brain, which causes fatigue through serotonin synthesis [14], BCAA supplementation counteracts this [15].
  • Recovery following surgery: logically, BCAAs are also of importance during the period of post-surgical regeneration. During this period, a lot of new tissue has to be produced.
     Studies have not revealed an unequivocal conclusion in relation to burns [7].
  • Sepsis: in sepsis, parenteral administration of BCAAs seems to have a positive effect on the nitrogen balance. This is probably associated with reduced muscle breakdown and improved protein synthesis [7].
  • Tardive dyskinesia: clinical research has revealed that a reduced capacity of removeing the amino acid phenylalanine from plasma is linked to symptoms of tardive dyskenisia in men. Taking BCAAs reduces the phenylalanine levels and the availability for the brain. Also in clinical research, BCAA supplementation is found to be able to lower the phenylalanine levels and to be able to significantly reduce the symptoms of tardive dyskinesia [16].
  • Phenylketonuria (PKU): PKU is a genetic disorder where the enzyme that breaks down the amino acid phenylalanine is absent or does not function. Because of that, this amino acid accumulates in the blood and the cerebrospinal fluid, ultimately resulting in brain damage. As well as limitation the intake of phenylalanine, BCAA supplementation also seems to be effective in limiting the neuronal damage in PKU. BCAAs compete with phenylalanine to bind to the (active) transport system to the brain, because of which the absorption of phenylalanine into the brain is limited [17,18].
  • Liver disorders: acute liver failure goes hand in hand with low levels of BCAAs and high levels of aromatic amino acids and methionine in the circulation. These changes in amino acid metabolism play an important role in the pathogenesis of many complications of liver cirrhosis. When, as a result of that, acute hepatic encephalopathy occurs, BCAAs have to be administered parenterally [12,19].
  • Neurologiscal disorders: BCAAs have an effect on the availability of neurotransmitters and the production of fake neurotransmitters as a result of a surplus of them [1,10,11]. For that reason, the use in psychiatric syndromes such as bipolar disorder and depression speaks for itself. However, this is unknown territory in which considerable research still has to be conducted.
  • Fatigue: Increased serotonin levels are closely linked to fatigue [14]. On account of the effects of BCAAs on the availability of serotonin in the brain, BCAAs can potentially reduce symptoms of fatigue. This theory is currently undergoing further research [15].

Contra-indications

BCAAs can be counted amongst the best tolerated amino acid supplements in the event of a surplus. Although systematic investigation has not yet been performed, studies demonstrate that doses of three times the daily recommended dose of 5-10 grams a day (from food and potentially supplementation) are endured without any problems [20].

When supplementation of more than 500 mg of BCAAs per kg of body weight per day are given, the amounts of serotonin, noradrenaline and dopamine can become extremly low in the brain. The consequneces of that on the behaviour and the mind have, however, undergone minimal research [20]. At the recommended dose of BCAAs, no contra-indications or interactions are known.

Dosage

The branched chain amino acids are easily absorbed and compete against other amino acids during absorption. For that reason, BCAA amino acids have to be taken at least half an hour before meals. For sportsmen and women, the most important doses are those immediately before and after the training session. Doses usually vary from between 3000 and 5000 mg a day. During extremely heavy training sessions, competitions or during the muscle building stage, depending on the intensity of the exercise, a dose of 3-5 grams can be taken every half hour.
A similar recommendation applies if damaged muscles have to be supported during the healing process.
For some people, it may be advisible to take the BCAAs immediately before going to bed, as the risk of muscle breakdown is greatest at night. Furthermore, during the early hours of the night, the natural secretion of growth hormone is at its highest, which can support protein synthesis. However, people with problems falling to sleep or sleeping through are advised against taking higher doses of BCAAs shortly before going to bed. On account of the serotonin-lowering effect, these can intensify the sleeping problems.
BCAAs are sometimes taken in the form of whey proteins. That is because whey protein isolate and casein have the highest leucine concentrations. However, also present in whey proteins are other amino acids that can compete during absorption. It is therefore often better to take a BCAA remedy.
Furthermore, the trace element, zinc, which is of equal importance for the muscles should also be provided. Zinc is hardly present in milk protein. Other vitamins and mineral substances are also important for amino acid metabolism. The use of a good  formula, in addition to BCAAs, is therefore also advised.

References

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  2. Platell C, Kong SE, McCauley R, et al. Branched-chain amino acids. J Gastroenterol Hepatol. 2000;15(7):706-17
  3. Shimomura Y, Honda T, Shiraki M, et al. Branched-chain amino acid catabolism in exercise and liver disease. J Nutr. 2006;136(1 Suppl):250S-3S
  4. Garlick PJ. The role of leucine in the regulation of protein metabolism. J Nutr. 2005;135(6 Suppl):1553S-6S
  5. Layman DK, Walker DA. Potential importance of leucine in treatment of obesity and the metabolic syndrome. J Nutr. 2006;136(1 Suppl):319S-23S
  6. Blomstrand E, Eliasson J, Karlsson HK, et al. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006;136(1 Suppl):269S-73S
  7. De Bandt JP, Cynober L. Therapeutic use of branched-chain amino acids in burn, trauma, and sepsis. J Nutr. 2006;136(1 Suppl):308S-13S
  8. van Dam AC. Das sportliche Training hochqualifizierter Fechterinnen und Fechter aus der Sicht physischer und psychischer Leistungsfaktoren, Dissertation. Graz: Karl-Franzens-Universität; 1981
  9. Suryawan A, Hawes JW, Harris RA, et al. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr. 1998;68(1):72-81
  10. Fernstrom JD. Aromatic amino acids and monoamine synthesis in the central nervous system: influence of the diet. J Nutr Biochem. 1990;1(10):508-17
  11. James JH, Ziparo V, Jeppsson B, et al. Hyperammonaemia, plasma aminoacid imbalance, and blood-brain aminoacid transport: a unified theory of portal-systemic encephalopathy. Lancet. 1979;2(8146):772-5
  12. Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr. 2006;136(1 Suppl):295S-8S
  13. Calder PC. Branched-chain amino acids and immunity. J Nutr. 2006;136(1 Suppl):288S-93S
  14. Davis JM, Alderson NL, Welsh RS. Serotonin and central nervous system fatigue: nutritional considerations. Am J Clin Nutr. 2000;72(2 Suppl):573S-8S
  15. Newsholme EA, Blomstrand E. Branched-chain amino acids and central fatigue. J Nutr. 2006;136(1 Suppl):274S-6S
  16. Richardson MA, Bevans ML, Read LL, et al. Efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men. Am J Psychiatry. 2003;160(6):1117-24
  17. Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest. 1999;103(8):1169-78 
  18. Berry HK, Brunner RL, Hunt MM, et al. Valine, isoleucine, and leucine. A new treatment for phenylketonuria. Am J Dis Child. 1990;144(5):539-43
  19. Mascarenhas R, Mobarhan S. New support for branched-chain amino acid supplementation in advanced hepatic failure. Nutr Rev. 2004;62(1):33-8
  20. Baker DH. Tolerance for branched-chain amino acids in experimental animals and humans. J Nutr. 2005;135(6 Suppl):1585S-90S.