Branched chain amino acid

Research

Dietary BCAA supplementation has been used clinically to aid in the recovery of burn victims. However, a 2006 paper suggests that the concept of nutrition supplemented with all BCAAs for burns, trauma, and sepsis should be abandoned for a more promising leucine-only-supplemented nutrition that requires further evaluation.

Dietary BCAAs have been used in an attempt to treat some cases of hepatic encephalopathy. They can have the effect of alleviating symptoms, but there is no evidence they benefit mortality rates, nutrition, or overall quality of life.

Certain studies suggested a possible link between a high incidence of amyotrophic lateral sclerosis among professional American football players and Italian soccer players, and certain sports supplements including BCAAs. In mouse studies, BCAAs were shown to cause cell hyper-excitability resembling that usually observed in ALS patients. The proposed underlying mechanism is that cell hyper-excitability results in increased calcium absorption by the cell and thus brings about cell death, specifically of neuronal cells which have particularly low calcium buffering capabilities. Yet any link between BCAAs and ALS remains to be fully established. While BCAAs can induce a hyperexcitability similar to the one observed in mice with ALS, current work does not show if a BCAA-enriched diet, given over a prolonged period, actually induces ALS-like symptoms.

Blood levels of the BCAAs are elevated in obese, insulin resistant humans and in mouse and rat models of diet-induced diabetes, suggesting the possibility that BCAAs contribute to the pathogenesis of obesity and diabetes. BCAA-restricted diets improve glucose tolerance and promote leanness in mice, and promotes insulin sensitivity in obese rats.

Synthesis

Five enzymes play a major role in the parallel synthesis pathways for isoleucine, valine, and leucine: threonine dehydrogenase, acetohydroxyacid synthase, ketoacid reductoisomerase, dihydroxyacid dehygrogenase, and aminotransferase. Threonine dehydrogenase catalyzes the deamination and dehydration of threonine to 2-ketobutyrate and ammonia. Isoleucine forms a negative feedback loop with threonine dehydrogenase. Acetohydroxyacid synthase is the first enzyme for the parallel pathway performing condensation reaction in both steps – condensation of pyruvate to acetolacetate in the valine pathway and condensation of pyruvate and 2-ketobutyrate to form acetohydroxybtylrate in the isoleucine pathway. Next ketoacid reductisomerase reduces the accetohydroxy acids from the previous step to yield dihydroxyacids in both the valine and isoleucine pathways. Dihydroxyacid dehygrogenase converts the dihyroxyacids in the next step. The final step in the parallel pathway is conducted by amino transferase, which yields the final products of valine and isoleucine. A series of four more enzymes - isopropylmalate synthase, isopropylmalate isomerase, isopropylmalate dehydrogenase, and aminotransferase - are necessary for the formation of leucine from 2-oxolsovalerate.

Degradation

Degradation of branched-chain amino acids involves the branched-chain alpha-keto acid dehydrogenase complex (BCKDH). A deficiency of this complex leads to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products in the blood and urine, giving the condition the name maple syrup urine disease.

The BCKDH complex converts branched-chain amino acids into acyl-CoA derivatives, which after subsequent reactions are converted either into acetyl-CoA or succinyl-CoA that enter the citric acid cycle.

Enzymes involved are branched chain aminotransferase and 3-methyl-2-oxobutanoate dehydrogenase.

Cell Signaling

While most amino acids are oxidized in the liver, BCAAs are primarily oxidized in the skeletal muscle and other peripheral tissues. The effects of BCAA administration on muscle growth in rat diaphragm was tested, and concluded that not only does a mixture of BCAAs alone have the same effect on growth as a complete mixture of amino acids, but an amino acid mixture with all but BCAAs has no effect on rat diaphragm muscle growth. Administration of either isoleucine or valine alone had no effect on muscle growth, although administration of leucine alone appears to be nearly as effective as the complete mixure of BCAAs. Leucine indirectly activates p70 S6 kinase as well as stimulates assembly of the eIF4F complex, which are essential for mRNA binding in translational initiation. P70 S6 kinase is part of the mammalian target of rapamycin complex (mTOR) signaling pathway, and has been shown to allow adaptive hypertrophy and recovery of rat muscle. At rest protein infusion stimulates protein synthesis 30 minutes after start of infusion, and protein synthesis stays elevated for another 90 minutes. Infusion of leucine at rest produces a six hour stimulatory effect and increased protein synthesis by phosphorylation of p70 S6 kinase in skeletal muscles. Following resistance exercise, without BCAA administration, a resistance exercise session does not affect mTOR phosphorylation and even produces a decrease in Akt phosphorylation. Some phosphorylation of p70 S6 kinase was discovered. When BCAAs were administered following a training session, sufficient phosphorylation of p70 S6 kinase and S6 indicated activation of the signaling cascade.

BCAAs role in diabetes mellitus type 2

In addition to cell signaling, the mTOR pathway also plays a role in beta cell growth leading to insulin secretion. High glucose in the blood begins the process of the mTOR signaling pathway, which leucine plays an indirect role. The combination of glucose, leucine, and other activators cause mTOR to start signaling for the proliferation of beta cells and the secretion of insulin. Higher concentrations of leucine cause hyperactivity in the mTOR pathway, and S6 kinase is activated leading to inhibition of insulin receptor substrate through serine phosphorylation. In the cell the increased activity of mTOR complex causes eventual inability of beta cells to release insulin and an inhibitory effect on S6 kinase leading to insulin resistance in the cells, contributing to development of type 2 diabetes.

Both humans and rats were tested for prevalence of BCAA signatures leading to insulin resistance. Human subjects’ body mass index was compared to concentration of BCAAs in their diet, as well as insulin resistance level. It was determined that subjects considered obese had higher metabolic signatures of BCAAs and higher resistance to insulin than those lean individuals with a lower body mass index. In addition rats fed a diet high in BCAAs had increased rates of insulin resistance and impaired phosphorylation of enzymes within their muscles.

Metformin is able to activate AMP kinase which phosphorylates proteins involved in the mTOR pathway, as well as leads to the progression of mTOR complex from its inactive state to its active state. It is suggested that metformin acts as a competitive inhibitor to the amino acid leucine in the mTOR pathway.

Uses in bodybuilding

Some bodybuilders believe branched-chain amino acid supplements may benefit muscle development, but the benefits of such supplements are unproven.