Branched-chain Amino Acids. Their benefits on our bodies.
Alberto Nascè
General information about BCAA
Branched chain amino acids have a non-continuous link of carbon bonds. Essentially having one carbon not in a linear fashion makes a branched point; all BCAA have one or more points of non-continuous links.
Leucine, isoleucine and valine are the three essential branched-chain amino acids.
Proteins derive from amino acids. In order to render amino acids form protein molecules, proteins must be digested via the gastrointestinal tract, GI. Most amino acids are then subject to transportation to the liver and some metabolism in the viscera area and the stomach mucosa. The majority of amino acids can be broken down in the liver, with the exception of BCAA. As a matter of fact, the liver oxidizes the BCAA from their converted form called oxo-ketoacids. Although the liver plays a very important part in the oxidization of BCAA, the largest percentage of it occurs in the muscle tissue.
It is known that these amino acids, particularly leucine, have anabolic potential by stimulating the initiation of protein translation, possibly suppressing/attenuating muscle proteolysis, and offering its transamination product alphaketoisocaproate (α-KIC), widely known to inhibit the enzymatic activity of the branched-chain alpha-keto dehydrogenase complex (BCKDH) which increases BCAA oxidation. Thus, BCAA supplementation could promote interesting effects on muscle repair by reducing protein oxidation, promoting muscle sarcomerogenesis, and improving muscle functional status.
BCAA and diet
The branched-chain amino acids make up 40% of the daily requirements of essential amino acids. While the dose of leucine is approximately 40mg per kilogram of body weight per day, and isoleucine and valine are tipically 10-30mg per kilogram per day. The established values for amino acids come from the FAO (Food and Agriculture Organization) and the NRC (National Research Council).
Food sources for BCAA are: whey, milk proteins, beef, chicken, fish, soy proteins, eggs, baked beans, whole wheat, brown rice, almonds, brazil nuts, pumpkin seeds, lima beans, chick peas, cashew nuts, lentils and corn.
BCAA: effects on muscles
Skeletal muscle damage is a phenomenon that can occur due to several factors, such as rupture and/or cell necrosis, representing about 10-55% of total muscular injuries. The main feature of skeletal muscle damage without cell necrosis is the disruption of muscle fibers, specifically the sheath of basal lamina. Regarding mechanical stimuli, specifically resistance exercise (RE), it is known that it can promote microdamage in muscle fibers imposed by contractions and/or overload and, according to the intensity, length, and volume the severity and degree of damage and muscle discomfort may be compounded over time and persist chronically. As functional consequence, muscle damage is manifested by a temporary decrease in strength, increased muscle passive tension, delayed onset muscle soreness (DOMS) and edema.
The damage of muscle tissue can be defined as the disruption of plasma membrane accompanied by the loss of muscle proteins (i.e. creatine kinase , myoglobin , lactate dehydrogenase , aldolase , troponin), the influx of serum proteins, increased population of inflammatory infiltrates in the muscle fibers (i.e. macrophages and neutrophils), DOMS, functional impairment (strength loss), and possible structural disorders such as sarcomere Z lines disarrangement.
Current literature classifies the damage of skeletal muscle in two stages called primary and secondary damage. The primary damage can be subdivided into two possible mechanisms: metabolic and mechanical. The metabolic damage has been proposed as a result of ischemia or hypoxia during prolonged exercise, which may result in changes in ion concentration, accumulation of metabolic wastes, and deficiency of adenosine triphosphate (ATP). Mechanical stimuli, however, may induce muscle damage as direct consequence of overload of muscle fibers or inappropriate balance of exercise variables that can cause the disruption of the sarcomeric Z line. The secondary damage can be manifested through processes associated with exercise that can lead to disruption of intracellular calcium homeostasis and systemic and local inflammatory response. However, it has been proposed that RE-induced muscle damage may be a necessary step to favor muscle remodeling and adaptation.
Recent studies suggest that BCAA supplementation may improve the repair of RE-induced damage muscle tissue. Shimomura et al. assessed serum free amino acids concentration in young untrained women supplemented with BCAA (5.5g BCAA in 1.0g of green tea) 15 minutes prior to performing a squat exercise (7 steps of 20 repetitions). The authors observed that serum BCAA concentrations were significantly decreased in the placebo group when compared to the supplemented group (2.2 fold higher), suggesting that the exercise protocol induced significant BCAA oxidation and the supplementation prevented such effect. Furthermore, another study from the same group found that BCAA supplementation (5g) 15 minutes before the same RE protocol reduced the peak time of muscle soreness (2-3 days after exercise) in young women by about 45% when compared to the placebo group (dextrin) and this reduction was significant up to 5 days after exercise. These data demonstrate that the RE-induced muscle damage increases BCAA uptake from serum to skeletal muscle, in order to be used as energy source and/or participate in muscle remodeling. Functionally, this appears to have some consequence in muscle pain. Exercise, in fact, activates the muscle BCKDH complex, resulting in enhanced BCAA catabolism. Therefore, exercise may increase the BCAA requirement. It has been reported that BCAA supplementation before exercise attenuates the breakdown of muscle proteins during exercise in humans and that leucine strongly promotes protein synthesis in skeletal muscle in humans and rats, suggesting that a BCAA supplement may attenuate muscle damage induced by exercise and promote recovery from the damage. Leucine manages to increase proteins production through a mechanism dependent on insulin and IGF-1: it stimulates the hormone which encourages the uptake of all amino acids included BCAA. Another test proved that subjects who ingested a branched-chain amino acids mixture during 4 days post exercise presented reduction of serum CK (from 48 to 96 hours), myoglobin (from 24 to 96 hours), and of muscle soreness (from 24 to 96 hours) when compared with the placebo group. However, although no significant differences were observed between groups in isometric maximal voluntary contraction, the muscle discomfort decreased more rapidly in the supplemented group. These results demonstrate that BCAA supplementation may attenuate muscle soreness and this can be related with some biochemical markers. However, since no results were observed in muscle strength, it is possible to postulate that the benefits of BCAA do not involve structural modulation.
Fatigue determines glycogen depletion, but ATP levels are maintained by BCAA degradation and fatty acid utilization. The effect of BCAA as energy is approximately 3-18% and possibly more depending on duration and intensity of workout. Muscle tissue oxidizes leucine and converts it into glutamine or alanine for blood energy. Glutamine and alanine can be converted into glucose. Also isoleucine and valine can be converted into Krebs cycle components for energy as well. BCAA are also able to prevent central fatigue in the nervous system. Central fatigue happens with the uptake of tryptophan by the brain, increasing the level of serotonin, which leads to tiredness demanding rest. BCAA inhibit the brain’s ability to uptake tryptophan.
Other recent works indicate that BCAA supplementation recovers peripheral blood mononuclear cell proliferation in response of mitogens after a long distance intense exercise, as well as plasma glutamine concentration. The BCAA also modifies the pattern of exercise-related cytokine production, leading to a diversion of the lymphocyte immune response towards a Th1 type. According to these findings, it is possible to consider the BCAA as a useful supplement for muscle recovery and immune regulation for sports events.
BCAA in burn, trauma and sepsis
The metabolic response to acute injury is mainly represented by an increase in metabolic rate and a reprioritization of body fuel utilization in favor of the visceral organs. This is demonstrated by accelerated metabolic rates, increased nitrogen loss and loss of lean body mass, stimulated acute-phase protein synthesis in the liver, and abnormalities in lipid and carbohydrate metabolism. If left unchecked, this metabolic response to stress could lead to malnutrition, which will worsen the stress situation by increasing the patient’s susceptibility to infection. At first, this unfavorable change is related to the mobilization and progressive depletion of the body’s protein stores. Hence, a catabolic insult, such as trauma, burn or sepsis induces a marked, generalized net protein catabolism in the muscle, as indicated by increased nitrogen loss and excretion of urinary 3-methylhistidine (3MH, a marker of myofibrillar catabolism). Depending on the catabolic insult and its severity, this loss in muscle protein results from decreased, normal, or even increased protein synthesis, which in the latter case, remains insufficient to compensate for higher proteolysis. This accelerated protein breakdown is associated with inhibited uptake of amino acids by the muscles, leading to a increased flux of amino acids from the periphery to the liver. In parallel, hepatic uptake of AAs is stimulated and protein synthesis and gluconeogenesis in the liver are enhanced. The alteration in nitrogen and protein metabolism represent a major threat for the organism. Therefore, a therapy able to promote anabolism or slow down protein degradation would constitute a major step forward. In this context, experiments have shown that the BCAA leucine, isoleucine and valine promote muscle protein synthesis and reduce protein catabolism.
By the way, the ability of BCAA to dampen protein loss in burn injury was not evident, as suggested by an initial study by Odessey and Parr. They used a model of mild thermal injury in young rats that associated increased protein breakdown limited to the injured limb with preserved protein synthesis. In isolated muscle from the unburned limb, leucine displayed its normal inhibitory effect on protein degradation; however, in muscle from the burned hind limb, leucine was ineffective. Taking into account the relative proportionality between injury severity and metabolic response, this did not predict favorable results in severe burns. The potential benefits of in vivo BCAA supplementation was further tested in 2 experimental studies. In severely burned (30% full thickness flame burn) guinea pigs receiving enteral nutrition, Mochizuki et al. studied the effect of various protein loads (whey protein, 10 to 30%) supplemented or not with BCAA. 14 days post-burn, the 10% groups were severely malnourished, and the 30% protein BCAA-supplemented group displayed digestive intolerance. In the 20% groups, BCAA supplementation did not improve weight gain, carcass and muscle (gastrocnemius) weights, albumin and cumulative nitrogen balance. In rats subjected to 15% full thickness scald burns and receiving total parental nutrition, Mori et al. compared two diets with 45% and 21% of BCAA. They observed a faster improvement in hepatic glycogen and protein and in muscle protein contents as well as in protein catabolism (assessed by the measurement of 3MH urinary excretion) in the BCAA supplemented group.
There are no available data on the effects of BCAA supplementation in experimental nonseptic non-surgical trauma injury. Among the 7 available studies performed on trauma patients, 6 administered BCAA-supplemented nutritional support and 1 administered leucine-supplemented nutritional support. Three concluded that BCAA supplementation was beneficial. However, interpretation of the results is made difficult by the heterogeneity of the patients included in these studies (multiple trauma, surgery, etc.) and by the absence in some studies of a balanced nutritional support or detailed composition of the support provided.
The efficiency of BCAA supplementation during sepsis has been repeatedly evaluated. From a pathophysiological point of view, Hasselgren et al. demonstrated that the ability of leucine and ketoisocaproate to modulate protein metabolism was significantly affected by sepsis. Using the model of incubated isolated muscle from rats made septic by cecal ligation and puncture, they observed that the concentration of leucine required to stimulate protein synthesis was 2-fold higher during sepsis compared with normal muscle. However, protein breakdown was unaffected by leucine or ketoisocaproate even at very high concentrations.
Side effects of BCAA
Changes in plasma aromatic amino acids (AAA: phenylalanine, tryptophan, tyrosine) and branched-chain amino acids levels (BCAA: isoleucine, leucine, valine) possibly influencing intracranial pressure (ICP) and cerebral oxygen consumption (SjvO2) were investigated in 19 sedated patients up to 14 days following severe traumatic brain injury (TBI). Contrary to the initial assumption that elevated AAA and decreased BCAA levels are detrimental, increased plasma phenylalanine levels were associated with beneficial signs in terms of decreased ICP and reduced cerebral oxygen consumption reflected by increased SjvO2; concomitantly, elevated plasma isoluecine and leucine levels were associated with increased ICP while leucine and valine were associated with decreased SjvO2 following severe TBI.
References
A primer on branched-chain amino acids by S.Sowers, 2009 Huntington College of Health Science.
Theraputic use of branched-chain amino acids in burn, trauma and sepsis by J.P.De Bandt and L.Cynober, 2006 American Society for Nutrition.
Potential therapeutic effects of branched-chain amino acids supplementation on resistance exercise-based muscle damage in humans by C.R.da Luz, H. Nicastro, N.E. Zanchi, D.F.S. Chaves, A.H.Lancha, 2011 Laboratory of Applied Nutrition and Metabolism, School of Physical Education and Sports, University of São Paulo, São Paulo, Brazil.
Branched-chain amino acid supplementation does not enhance athletic performance but affects muscle recovery and the immune system by M.Negro, S.Giardina, B.Marzani, F.Marzatico, Pharmacobiochemistry Laboratory, Section of Pharmacology and Pharmacological Biotechnology, Department of Cellular and Molecules, Physiological and Pharmacological Sciences, University of Pavia, Pavia, Italy.
Nutraceutical effects of branched-chain amino acids on skeletal muscle by Y.Shimomura, Y.Yamamoto, G.Bajotto, J.Sato, T.Murakami, N.Shimomura, H.Kobayashi, K.Mawatari, Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya, Japan.
Changes in plasma phenylalanine, isoluecine, leucine and valine are associated with significant changes in intracranial pressure and jugular venous saturation in patients with severe traumatic brain injury by R.N.Vuille-Dit-Bille, R.Ha-Huy, J.F.Stover, Surgical Intensive Care Medicine, UniversitätsSpital Zürich, 8091, Zurich, Switzerland.
