Role Of Branched-chain Amino Acids Research Articles

Branched-chain amino acids and the association with type2 diabetes.

Branched-chain amino acids and the association with type2 diabetes.

Whole grains beyond fibre: what can metabolomics tell us about mechanisms?

Dietary fibre alone does not fully explain the frequent association between greater intake of whole grains and reduced risk of disease in observational studies, and other phytochemicals or food structure may also play an important role. For all the observational evidence for the benefits of a whole-grain-rich diet, we have only limited knowledge of the mechanisms behind this reduction in disease risk, aside from the action of specific cereal fibres on reduction of blood cholesterol and the post-prandial glucose peak. Nutritional metabolomics, the global measurement and interpretation of metabolic profiles, assesses the interaction of food with the endogenous gene-protein cascade and the gut microbiome. This approach allows the generation of new hypotheses which account for systemic effects, rather than just focusing on one or two mechanisms or metabolic pathways. To date, animal and human trials using metabolomics to investigate mechanistic changes to metabolism on eating whole grains and cereal fractions have led to new hypotheses around mechanistic effects of whole grains. These include the role of cereals as a major source of dietary glycine betaine, a possible effect on phospholipid synthesis or metabolism, the role of branched-chain amino acids and improvements in insulin sensitivity, and the possibility that whole grains may have an effect on protein metabolism. These hypotheses help explain some of the observed effects of whole grains, although mechanistic studies using stable isotopes and fully quantitative measures are required to confirm these potential mechanisms.

Metabolic and Physiological Roles of Branched-Chain Amino Acids

Branch chain amino acids (BCAAs) have unique properties with diverse physiological and metabolic roles. They have functions other than simple nutrition. Different diseases including metabolic disease lead to protein loss, especially muscle protein. Supplementation of BCAAs promotes protein synthesis and reduces break down, as well as improving disease conditions. They are important regulators of mTOR signaling pathway and regulate protein synthesis as well as protein turnover. BCAAs facilitate glucose uptake by liver and SK muscle and also enhance glycogen synthesis. Oxidation of BCAAs seems to be beneficial for metabolic health as their catabolism increases fatty acid oxidation and reduces risk of obesity. BCAAs are also important in immunity, brain function, and other physiological aspects of well-being. All three BCAAs are absolutely required for lymphocyte growth and proliferation. They are also important for proper immune cell function. BCAAs may influence brain protein synthesis, and production of energy and may influence synthesis of different neurotransmitters. BCAAs can be used therapeutically and future studies may be directed to investigating the diverse effects of BCAAs in different tissues and their signaling pathways.

Nutritional and regulatory role of branched-chain amino acids in lactation

Optimal growth and health of suckling neonates critically depend on milk production by their mothers. In both humans and animals, branched-chain amino acids (BCAA) are not only the major components of milk proteins but are also nitrogenous precursors for the synthesis of glutamate, glutamine, alanine, and aspartate in the mammary gland. These synthetic pathways, which are initiated by BCAA transaminase, contribute to the high abundance of free and peptide-bound glutamate, glutamine, aspartate and asparagine in milk. In mammary epithelial cells, the carbon skeletons of BCAA can be partially oxidized via branched-chain alpha-ketoacid dehydrogenase to provide energy for highly active metabolic processes, including nutrient transport, protein turnover, as well as lipid and lactose syntheses. In addition, results of recent studies indicate that BCAA play regulatory roles in mammary metabolism. For example, leucine can activate the mammalian target of rapamycin cell signaling pathway to enhance protein synthesis in mammary epithelial cells. Dietary supplementation with BCAA may have great potential to enhance milk synthesis by the lactating mammary gland, thereby improving neonatal survival, growth and development.

Reducing Muscle Soreness and Muscle Damage: A Role for Branched-Chain Amino Acids

Reducing Muscle Soreness and Muscle Damage: A Role for Branched-Chain Amino Acids

Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective

Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms - increased mitochondrial respiration and reduced production of oxygen radicals - is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk.

Abstract 984: The role of branched-chain amino acids (BCAAs) oxidation in the survival of brain metastatic breast cancer cells

Abstract Background: Glucose is the main source of energy for most cells. When the glucose is limited some cells can use amino acids to support their survival. This ability of oxidizing branched chain amino acids (BCAAs) of the brain metastatic breast cancer cells was investigated. Methods: Breast cancer cell lines, MDA-MB-231 cell and its brain metastatic derivative MDA-MB-Br3 were used in this study. The survivability, ability of oxidizing BCAAs and expression of BCAA oxidation related enzymes of these cells were determined. Results: MDA-MB-Br3 cells survived well and oxidized more BCAAs than MDA-MB-231 cells when cultured in glucose free medium. Accordingly, the activity of branched-chain a-ketoacid dehydrogenase complex of MDA-MB-Br3 cells is significantly higher than that of the MDA-MB-231 cells. Conclusions: The breast cancer cell line MDA-MB-Br3 can use BCAAs as a resource of energy for survival in the environment with very low level of glucose. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 984. doi:10.1158/1538-7445.AM2011-984

Leucine and Branched‐Chain Amino Acids Modulate Translation in Rat Primary Hepatocytes

We have previously demonstrated that high amino acids (AA) and insulin are required for stimulation of translation in hepatocytes. Three hepatic sensing pathways are regulated by dietary protein, i.e. mTOR, GCN2 and AMPK. However, the nature of the AA signal is still unknown. We aimed to identify this signal and clarify the relationship between the transduction pathways using primary hepatocyte culture. We examined the role of branched‐chain amino acids (BCAA) and L‐leucine (Leu) in these pathways. With similar findings to the ones we obtained upon high AA treatment, BCAA or Leu stimulated phosphorylation of mTOR, 4E‐BP1 and S6K1 and decreased phosphorylation of AMPK and GCN2. We further characterized the roles of mTOR and AMPK in the pathway by using AICAR, an activator of AMPK, and rapamycin, an inhibitor of mTOR. Our results show that AICAR not only induced AMPK phosphorylation with or without insulin, but also decreased mTOR phosphorylation. Rapamycin treatment further decreased mTOR phosphorylation. Surprisingly, 4E‐BP1, a well known target of mTOR was dramatically decreased by AICAR, but not by rapamycin. These results suggest that BCAA and Leu are the key amino acids sensed by hepatocytes, and that AMPK may act as a general switch during high AA thereby controlling protein synthesis. To characterize the hierarchy of the system more in detail we next aim to identify the protein phosphatases induced by high AA.

Branched-chain amino acids in liver disease: new aspects of long known phenomena

To provide an overview of findings on the role of branched-chain amino acids (BCAAs) in the pathophysiology, pathobiochemistry, and treatment of liver cirrhosis and its complications that have been published since or were not included in the last review on this topic in 2007 in this journal. There has been continued interest in the potential of oral BCAA supplements in improving energy metabolism, nitrogen metabolism, carbohydrate metabolism, insulin resistance, severity of liver disease, serum albumin levels, quality of serum albumin, or postoperative complication rates. Unfortunately, many trials suffer from lacking or inadequate controls or small sample size. In a fine example of scientific perseverance, Dutch researchers uncovered the long-known phenomenon of ingested blood being highly comagenic in patients with cirrhosis to be due to the low biologic value of blood protein. The absence of isoleucine and the abundance of leucine in the hemoglobin molecule by way of BCAA antagonism leads to impaired protein synthesis and azotemia paving the way for hepatic encephalopathy. Recognizing hypoisoleucinemia and BCAA antagonism following gastrointestinal bleeding, and its successful treatment by isoleucine infusion has advanced our understanding of the role of BCAA in liver cirrhosis.

Role of branched-chain amino acids in liver disease: the evidence for and against

There is ample evidence that patients with liver disease have an ongoing energy and protein catabolism. Nutritional management in these patients must receive high priority. The administration of branched-chain amino acids to patients with liver disease has been a controversial subject. This review is an update on the data available from various studies involving branched-chain amino acids supplementation in patients with chronic liver disease and associated complications. This review summarizes the results of nutritional interventions involving branched-chain amino acids supplementation carried out in different centres around the world. It is interesting to note that no toxic effects of branched-chain amino acids supplementation have been reported in any of these trials. Administration of branched-chain amino acids stimulates hepatic protein synthesis in patients with chronic liver disease and this could contribute significantly to improving their nutritional status, and result in a better quality of life. The beneficial role of branched-chain amino acids supplementation in patients with chronic hepatic encephalopathy has been clearly documented in some studies but the exact mechanism of action is still not clear.

A Role for Branched-Chain Amino Acids in Reducing Central Fatigue

Several factors have been identified to cause peripheral fatigue during exercise, whereas the mechanisms behind central fatigue are less well known. Changes in the brain 5-hydroxytryptamine (5-HT) level is one factor that has been suggested to cause fatigue. The rate-limiting step in the synthesis of 5-HT is the transport of tryptophan across the blood-brain barrier. This transport is influenced by the fraction of tryptophan available for transport into the brain and the concentration of the other large neutral amino acids, including the BCAAs (leucine, isoleucine, and valine), which are transported via the same carrier system. Studies in human subjects have shown that the plasma ratio of free tryptophan (unbound to albumin)/BCAAs increases and that tryptophan is taken up by the brain during endurance exercise, suggesting that this may increase the synthesis of 5-HT in the brain. Ingestion of BCAAs increases their concentration in plasma. This may reduce the uptake of tryptophan by the brain and also 5-HT synthesis and thereby delay fatigue. Accordingly, when BCAAs were supplied to human subjects during a standardized cycle ergometer exercise their ratings of perceived exertion and mental fatigue were reduced, and, during a competitive 30-km cross-country race, their performance on different cognitive tests was improved after the race. In some situations the intake of BCAAs also improves physical performance. The results also suggest that ingestion of carbohydrates during exercise delays a possible effect of BCAAs on fatigue since the brain's uptake of tryptophan is reduced.

Hormonal and Signaling Role of Branched-Chain Amino Acids

Amino acids (AAs), especially BCAAs, play pivotal roles in hormonal secretion and action as well as in intracellular signaling. There is emerging data showing that BCAAs regulate gene transcription and translation. Signaling proteins such as the mammalian target of rapamycin act as sensors of BCAAs, especially leucine, to modulate anabolic action. AAs stimulate protein synthesis and inhibit protein breakdown in skeletal muscle and liver. The specific role of BCAAs in regulating synthesis and breakdown of individual protein or proteins with common function or functions remains to be defined. Future studies should also focus on potential adverse effects of BCAAs on insulin sensitivity, renal function, and tumor growth. It also remains to be determined whether potential adverse effects of BCAA supplementation is similar in people of different age groups.

The metabolic role of branched-chain amino acids

14 C] leucine entering the tissue is decarboxylated in the diaphragm and that a considerable proportion is degraded even further. The percentages of decarboxylation for isoleucine (58%) and valine (31%) also were substantial. Addition of insulin brought about a small but consistent stimulation of leucine oxidation. Moreover, the fraction of isotope taken up by the diaphragm appearing as 14 CO2 did not decline markedly as the concentration of amino acids supplied rose, in contrast with the amount of isotope incorporated into protein, which dropped steadily as the specific activity fell. 3 Further extensive work exploring the possibility that oxidation might be a major metabolic pathway for leucine (and possibly all three BCAAs) in rat diaphragm and in soleus and extensor digitorm longus muscles was published in 1972 by Odessey and Goldberg.4 They determined that the diaphragm posseses a marked ability to degrade leucine 1- 14 Ct o 14 CO2. The metabolism of leucine by the diaphragm depended on the concentration, and leucine uptake and oxidation increased with increasing external concentrations. Further, the amount of leucine degradation relative to its incorporation into protein increased 10-fold as its external concentration was raised. The red soleus and pale extensor degitorum longus muscles exhibited a similar marked capacity for leucine oxidation. The rates of CO2 production, incorporation into protein, and total uptake in these two muscles were lower than those in the diaphragm. The skeletal muscle mass, which constitutes 43% of the body mass, is the major site for leucine oxidation in the body, marking leucine and possibly the other BCAAs as significant energy sources for the muscle. Complete oxidation of leucine in the muscle yields more adenosine triphosphate molecules on a molar basis than complete oxidation of glucose. Further, this inherent ability of muscle to oxidize leucine increases under certain physiologic states such as food deprivation. 5 Later work determined that the rate of oxidation of BCAA in muscle is under metabolic and hormonal regulation. Buse and Reid6 in skeletal muscle and Chua et al.7 in cardiac muscle suggested that leucine also regulates the turnover of protein in muscle cells by inhibiting protein degradation and enhancing protein synthesis. This regulation of muscle protein turnover by leucine influences the transition to negative

Function of Leucine in Excitatory Neurotransmitter Metabolism in the Central Nervous System

A novel hypothesis for the role of branched-chain amino acids (BCAA) in regulating levels of the major excitatory neurotransmitter glutamate in the central nervous system is described. It is postulated that the branched-chain aminotransferase (BCAT) isoenzymes (mitochondrial BCATm and cytosolic BCATc) are localized in different cell types and operate in series to provide nitrogen for optimal rates of de novo glutamate synthesis. BCAA enter the astrocyte where transamination is catalyzed by BCATm, producing glutamate and branched-chain alpha-keto acids (BCKA). BCKA, which are poorly oxidized in astrocytes, exit and are taken up by neurons. Neuronal BCATc catalyzes transamination of the BCKA with glutamate. The products, BCAA, exit the neuron and return to the astrocyte. The alpha-ketoglutarate product in the neurons may undergo reductive amination to glutamate via neuronal glutamate dehydrogenase. Operation of the shuttle in the proposed direction provides a mechanism for efficient nitrogen transfer between astrocytes and neurons and synthesis of glutamate from astrocyte alpha-ketoglutarate. Evidence in favor of the hypothesis is: 1) The two BCAT isoenzymes appear to be localized separately in the neurons (BCATc) or in the astroglia (BCATm). 2) Inhibition of the shuttle in the direction of glutamate synthesis can be achieved by inhibiting BCATc using the neuroactive drug gabapentin. Although gabapentin does not inhibit BCATm, it does block de novo glutamate synthesis from alpha-ketoglutarate. 3) Conversely, gabapentin stimulates oxidation of glutamate. Inhibition of BCATc may allow BCKA to accumulate in the astroglia, thus facilitating conversion of glutamate to alpha-ketoglutarate.

The role of branched-chain amino acids and aromatic amino acids of various tissues and the degenerations of skeletal muscle fiber in liver cirrhosis model rat

The role of branched-chain amino acids and aromatic amino acids of various tissues and the degenerations of skeletal muscle fiber in liver cirrhosis model rat

Branched-chain amino acid catabolism and cancer cachexia (review)

The present study focuses on the role of branched-chain amino acids (BCAA) (leucine, isoleucine and valine) in cancer cachexia. This is a frequent and devastating complication of cancer occurring in more than two thirds of patients who die with advanced cancer, and in up to 22% of cancer deaths it is the only abnormality found at autopsy. BCAA are essential amino acids often increased in cancer patients and this phenomenon may be related with increased protein degradation in skeletal muscle and consequently, cancer cachexia. The relevance of this association in medical terms is evident, future investigations may focus on therapeutical strategies based on the administration of BCAA to cachectic patients.

Precursor role of branched-chain amino acids in the biosynthesis of iso and anteiso fatty acids in rat skin

Monoester fraction of rat skin surface lipid has been shown to contain more than trace amounts of branchedlong-chain fatty acids (BCFAs) of the iso and anteiso series. These BCFAs are biosynthesized using either branched-chain amino acids (BCAAs) or branched-chain α-keto acids (BCKAs), or using both of them as precursor. This study has been carried out to address which precursor, BCAAs or BCKAs in the circulation, are mainly utilized for biosynthesis of BCFAs. Dietary supplement of [ 14C]-valine and isoleucine-induced sharp rise of serum concentration of these two amino acids and their respective α-keto acids, and elevated the levels of related BCFAs and branched-chain fatty alcohols in the monoester fraction. A larger proportion of label in the total skin surface lipid was found in the monoester fraction in which fatty acid and alcohol accounted for approx. 80% of total radioactivity. Incorporation of intravenously administered [ 14C]-BCAAs and BCKAs into the monoester fraction revealed that BCAAs were far better as precursors than BCKAs for BCFA biosynthesis in rat skin. Among three BCAAs, leucine differed from valine or isoleucine in that this amino acid was primarily utilized for production of straight-chain fatty acids rather than for production of related BCFA.

Comparative metabolism of branched-chain amino acids to precursors of juvenile hormone biogenesis in corpora allata of lepidopterous versus nonlepidopterous insects.

Comparative studies were performed on the role of branched-chain amino acids (BCAA) in juvenile hormone (JH) biosynthesis using several lepidopterous and nonlepidopterous insects. Corpora cardiaca-corpora allata complexes (CC-CA, the corpora allata being the organ of JH biogenesis) were maintained in culture medium containing a uniformly 14C-labeled BCAA, together with [methyl-3H]methionine as mass marker for JH quantification. BCAA catabolism was quantified by directly analyzing the medium for the presence of 14C-labeled propionate and/or acetate, while JHs were extracted, purified by liquid chromatography, and subjected to double-label liquid scintillation counting. Our results indicate that active BCAA catabolism occurs within the CC-CA of lepidopterans, and this efficiently provides propionyl-CoA (from isoleucine or valine) for the biosynthesis of the ethyl branches of JH I and II. Acetyl-CoA, formed from isoleucine or leucine catabolism, is also utilized by lepidopteran CC-CA for biosynthesizing JH III and the acetate-derived portions of the ethyl-branched JHs. In contrast, CC-CA of nonlepidopterans fail to catabolize BCAA. Consequently, exogenous isoleucine or leucine does not serve as a carbon source for the biosynthesis of JH III by these glands, and no propionyl-CoA is produced for genesis of ethyl-branched JHs. This is the first observation of a tissue-specific metabolic difference which in part explains why these novel homosesquiterpenoids exist in lepidopterans, but not in nonlepidopterans.

Kinetics of inhibition of rat liver and kidney arginases by proline and branched-chain amino acids

The effects of proline, leucine, isoleucine and valine on kidney and liver arginases were studied. At pH 7.5 and at nearly physiological concentrations, the branched-chain amino acids caused a significant inhibition of liver arginase A 1 and only minor effects on kidney arginase A 4. Kidney arginase was, however, much more sensitive to inhibition by proline than the liver enzyme. The inhibition of liver and kindey arginases by branched-chain amino acids was partial, indicating the existence of allosteric sites on both enzymes. The function of kidney arginase in proline biosynthesis and a possible role of branched-chain amino acids in the hydrolysis of arginine in liver is discussed.

On the role of branched-chain amino acids in protein turnover of skeletal muscle. Studies in vivo with L-norleucine.

The effect of L-norleucine, an isomer of leucine, on protein metabolism in vivo was studied in suckling rats. Rats were injected subcutaneously with various doses of L-norleucine (0.5 and 5.0 mumol/g body wt.) every 12 h from 3 to 15 days post partum. Protein concentration, amino acid concentrations, and incorporation of [3H]tyrosine into protein were analyzed in liver, muscles of thigh and small intestine. Amino acid concentrations and insulin levels in serum were also measured. At 5 days of age, norleucine induced an increase in protein concentration of skeletal muscle with an increased incorporation of [3H]tyrosine into protein indicating an accelerated protein synthesis. Changes in protein metabolism were paralleled by alterations in the amino acid pattern of this tissue. When protein concentration and protein synthesis were increased in skeletal muscle, protein concentration of small intestine was decreased, accompanied by elevated levels of amino acids in tissue. Protein synthesis of small intestine was not altered by the norleucine treatment. The results suggest a close interrelationship between skeletal muscle and small intestine with respect to protein turnover. The effects of norleucine were less pronounced at 10 and 15 days of age, which indicates a metabolic adaptation to the treatment. Alterations in amino acid concentrations of tissue due to changes in protein metabolism were not uniform but tissue-specific. Current concepts for explaining the effects of branched-chain amino acids (BCAA) on protein turnover in skeletal muscle are based on the assumption that the BCAA or leucine alone might become rate-limiting for protein synthesis in muscle under catabolic conditions. The amino acid analogue norleucine, however, cannot replace any of the BCAA in protein. Additionally, norleucine affected protein metabolism in highly anabolic organisms. Therefore, the present thoughts on this issue appear to be incomplete.