Effect of branched-chain amino acids on nitrogen metabolism in irradiated rats

The influence of a mixture of amino acids, with a branched chain, on the protein-nitrogen metabolism in irradiated animals was investigated. Repeated intraperitoneal administrations of the drug was shown to reduce the severity of radiation affection and to normalize nitrogen metabolism decreasing the postirradiation nitrogen losses by the organism.     

Portal-drained viscera and hepatic fluxes of branched-chain amino acids do not account for differences in circulating branched-chain amino acids in rats fed arginine-deficient diets

Summary Concentrations and fluxes of amino acids across the portal-drained viscera (PDV) and liver were assessed in rats fed a meal of one of three arginine-deficient diets containing either alanine or the arginine precursors, ornithine or citrulline. A previous report included findings of seven arginine-related amino acids and indicated that only the citrulline-containing diet protected blood arginine concentrations. In the present report we extend these findings and note that the concentrations and fluxes of the non-arginine-related amino acids showed remarkable consistency across diet groups. However, total branched-chain amino acid (BCAA) concentrations of arterial blood were higher in rats fed the - Arg/+ Ala and the - Arg/+ Orn diets than in rats fed the control (+ Arg) diet. The elevated BCAA correlated with higher circulating concentrations of other essential amino acids but were inversely correlated with arginine concentrations. PDV and hepatic fluxes of BCAA were not different across diet groups, indicating that amino acid absorption and hepatic utilization of BCAA were generally comparable across diet groups. Hepatic concentrations of 14 of 22 measured amino acids, including total BCAA, were correlated with their arterial concentrations. The circulating concentrations and net PDV and hepatic fluxes of rats fed the control diet were comparable to our previous observations in fed rats and illustrate the role of the liver in utilization of diet-derived essential amino acids.Abbreviations PDV portal-drained viscera - BCAA branched-chain amino acids - SSA 5-sulfosalicylic acid - PBF portal blood flow - HBF hepatic blood flow - SELSM pooled standard errors of least squares means - TAA total amino acids - NEAA nonessential amino acids - EAA essential amino acids - LNAA large neutral amino acids Mention of a trade name, proprietary product or specific equipment does not constitute a guarantee by the US Department of Agriculture and does not imply its approval to the exclusion of other products that may be suitable.     

Metabolism of branched-chain amino acids in starved rats: the role of hepatic tissue

Parameters of branched-chain amino acids (BCAA; leucine, isoleucine and valine) and protein metabolism were evaluated using L-[1-(14)C]leucine and alpha-keto[1-(14)C]isocaproate (KIC) in the whole body and in isolated perfused liver (IPL) of rats fed ad libitum or starved for 3 days. Starvation caused a significant increase in plasma BCAA levels and a decrease in leucine appearance from proteolysis, leucine incorporation into body proteins, leucine oxidation, leucine-oxidized fraction, and leucine clearance. Protein synthesis decreased significantly in skeletal muscle and the liver. There were no significant differences in leucine and KIC oxidation by IPL. In starved animals, a significant increase in net release of BCAA and tyrosine by IPL was observed, while the effect on other amino acids was non-significant. We conclude that the protein-sparing phase of uncomplicated starvation is associated with decreased whole-body proteolysis, protein synthesis, branched-chain amino acid (BCAA) oxidation, and BCAA clearance. The increase in plasma BCAA levels in starved animals results in part from decreased BCAA catabolism, particularly in heart and skeletal muscles, and from a net release of BCAA by the hepatic tissue.     

Effects of branched-chain amino acids on plasma amino acids in amyotrophic lateral sclerosis

Summary Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, biological findings suggest that the excitatory amino acid glutamate contributes to the pathogenesis of ALS. In previous studies of ALS, the therapeutic effect of the branched-chain amino acids (BCAAs) leucine, valine and isoleucine has been evaluated. The present study aimed at investigating the acute effect of BCAAs on plasma glutamate levels in ALS patients. Following two oral doses of BCAAs, significantly increased plasma levels were seen for valine (500%), isoleucine (1,377%) and leucine (927%), however the plasma level of glutamate was not affected. The plasma level of several other amino acids (tryptophan, tyrosine, phenylalanine and methionine) were found decreased after oral BCAAs, which may indicate a diminution in the rate of degradation of muscle protein and/or an increase in tissue disposal of amino acids.     

Regulation of global and specific mRNA translation by oral administration of branched-chain amino acids

The importance of branched-chain amino acids as nutrient regulators of protein synthesis in skeletal muscle was recognized more than 20 years ago. Of the branched-chain amino acids, leucine in particular was shown to play a central role in promoting muscle protein synthesis. However, it was only recently that the mechanism(s) involved in the stimulation of protein synthesis by leucine has begun to be defined. Studies performed in our laboratory during the past few years have revealed that oral administration of leucine to fasted rats enhances protein synthesis in association with increased phosphorylation of two proteins downstream of the protein kinase referred to as the mammalian target of rapamycin (mTOR). These proteins, eukaryotic initiation factor eIF4E binding protein (4E-BP)1 and ribosomal protein S6 kinase S6K1, control in part the step in translation initiation involving the binding of mRNA to the 40S ribosomal subunit. In theory the translation of all mRNAs can be regulated through such mechanisms, however, some mRNAs are more sensitive to the changes than others, resulting in modulation of gene expression through altered patterns of translation of specific mRNAs. Moreover, although a basal amount of plasma insulin is required for leucine to enhance signaling downstream of mTOR, the concentration observed in plasma of fasted rats is sufficient to observe maximal changes in phosphorylation of 4E-BP1 and S6K1.     

Evolution of the biosynthesis of the branched-chain amino acids

The origin of the biosynthetic pathways for the branched-chain amino acids cannot be understood in terms of the backwards development of the present acetolactate pathway because it contains unstable intermediates. We propose that the first biosynthesis of the branched-chain amino acids was by the reductive carboxylation of short branched chain fatty acids giving keto acids which were then transaminated. Similar reaction sequences mediated by nonspecific enzymes would produce serine and threonine from the abundant prebiotic compounds glycolic and lactic acids. The aromatic amino acids may also have first been synthesized in this way, e.g. tryptophan from indole acetic acid. The next step would have been the biosynthesis of leucine from -ketoisovaleric acid. The acetolactate pathway developed subsequently. The first version of the Krebs cycle, which was used for amino acid biosynthesis, would have been assembled by making use of the reductive carboxylation and leucine biosynthesis enzymes, and completed with the development of a single new enzyme, succinate dehydrogenase. This evolutionary scheme suggests that there may be limitations to inferring the origins of metabolism by a simple back extrapolation of current pathways.     

Transport of branched-chain amino acids in Corynebacterium glutamicum

The transport of branched-chain amino acids was characterized in intact cells of Corynebacterium glutamicum ATCC 13032. Uptake and accumulation of these amino acids occur via a common specific carrier with slightly different affiniteis for each substrate (K _m[Ile]=5.4 M, K _m[Leu]=9.0 M, K _m[Val]=9.5 M). The maximal uptake rates for all three substrates were very similar (0.94–1.30 nmol/mg dw · min). The optimum of amino acid uptake was at pH 8.5 and the activation energy was determined to be 80 kJ/mol. The transport activity showed a marked dependence on the presence of Na⁺ ions and on the membrane potential, but was independent of an existing proton gradient. It is concluded, that uptake of branched-chain amino acid transport proceeds via a secondary active Na⁺-coupled symport mechanism.Abbreviations CCCP Carboxyl cyanide m-chlorophenylhydrazone - dw dry weight - MES 2[N-morpholino]ethanesulfonic acid - mon monensin - nig nigericin - TPP tetraphenylphosphonium bromide - Tris tris[hydroxymethyl]aminomethane - val valinomycin     

Effect of branched-chain amino acids on the irradiated body

The administration to rats of amino acids (valine, leucine, and isoleucine) for 10 days after whole-body X-irradiation with a dose of 7 Gy increased the survival rate and average life of animals and normalized some carbohydrate and nitrogen metabolism indexes. The insulin-like effect of these amino acids on glucose absorption by phrenic muscles of the exposed rats was detected.     

Insulin resistance and the metabolism of branched-chain amino acids in humans

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.     

Dietary deficiencies of single amino acids: Whole-body amino acid composition of adult rats

Abstract

To ascertain whether chronic amino acid deficiency alters the amino acid composition of the body, 44 adult female rats were randomly allocated to one of 11 treatments which included one control group, ingesting an adequate diet with balanced protein, and ten deficient groups in which one group received protein-deficient diets and the other groups consumed diets each deficient in a single essential amino acid. The degree of deficiency was adjusted to achieve a gradual decline in body weight to 85% of the initial weight and was then adjusted so that this weight was maintained until the end of the experiment at 93 days, when the rats were killed. Deficient rats had lower absolute weights of liver, gastrointestinal tract and muscle than animals given the adequate diet but greater relative weights (% of body weight) of heart and kidneys. There were no significant differences amongst groups in percentages of lipid, nitrogen, protein plus lipid or dry matter. Chronic marginal amino acid deficiencies did not selectively alter amino acid composition.     

Dietary deficiencies of single amino acids: whole-body amino acid composition of adult rats

To ascertain whether chronic amino acid deficiency alters the amino acid composition of the body, 44 adult female rats were randomly allocated to one of 11 treatments which included one control group, ingesting an adequate diet with balanced protein, and ten deficient groups in which one group received protein-deficient diets and the other groups consumed diets each deficient in a single essential amino acid. The degree of deficiency was adjusted to achieve a gradual decline in body weight to 85% of the initial weight and was then adjusted so that this weight was maintained until the end of the experiment at 93 days, when the rats were killed. Deficient rats had lower absolute weights of liver, gastrointestinal tract and muscle than animals given the adequate diet but greater relative weights (% of body weight) of heart and kidneys. There were no significant differences amongst groups in percentages of lipid, nitrogen, protein plus lipid or dry matter. Chronic marginal amino acid deficiencies did not selectively alter amino acid composition.     

Interactions between the branched-chain amino acids in the growth of Spirodela polyrhiza

The joint action of L-valine and L-isoleucine, L-leucine and L-isoleucine, and L-valine and L-leucine on the growth of Spirodela polyrhiza was established. The effect of one branched-chain amino acid on growth inhibition by another one was compared with the non-specific antagonisms which glycine and L-alanine exert on growth inhibition by singly supplied branched-chain amino acids. In this way specific and non-specific interactions could be distinguished. It appeared that: (1) L-isoleucine was a specific antagonist of L-valine; (2) L-leucine was a specific antagonist of L-isoleucine; (3) L-valine and L-leucine were synergistic growth inhibitors. Further, it was found that: (4) growth inhibition by L-leucine was specifically antagonized by simultaneously supplied L-valine and L-isoleucine; (5) an excess of L-isoleucine strongly inhibited the conversion of exogenous valine into leucine; (6) accumulation of valine was typical of isoleucine-induced growth inhibition. The results are consistent with the view that growth inhibition by L-valine and L-leucine is due to the blocking of acetohydroxy acid synthetase, the first common enzyme in the valine-isoleucine biosynthetic pathway. Growth inhibition by L-isoleucine, however, seems to result from inhibition of leucine synthesis at a step after 2-oxoisovaleric acid. Some aspects of the regulation of branched-chain amino acid biosynthesis in higher plants are discussed.     

Regulation of protein synthesis by branched-chain amino acids in vivo

Recent advances in the understanding of mRNA translation have facilitated molecular studies on the regulation of protein synthesis by nutrients and the interplay between nutrients and hormonal signals. Numerous reports have established that, in skeletal muscle, the branched-chain amino acids (BCAAs) have the unique ability to initiate signal transduction pathways that modulate translation initiation. Of the BCAAs, leucine is the most potent. Oral administration of leucine to food-deprived rats enhances muscle protein synthesis, in part, through activation of the mRNA binding step of translation initiation. Interestingly, leucine signaling in skeletal muscle differs from that in liver, suggesting that the responses may be tissue specific. The purpose of this paper was to briefly review the current knowledge of how BCAAs act as regulators of protein synthesis in physiologically important tissues, with particular focus on the mechanisms by which BCAAs regulate translation initiation.