Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain (P < 0.05) and a 25% decrease in adiposity (P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL cholesterol were decreased by 27% (P < 0.001) and 53% (P < 0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum consumption of HFD likely via multiple mechanisms.

https://diabetes.diabetesjournals.org/content/diabetes/56/6/1647.full.pdf

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

Exercise-induced muscle damage (EIMD) can be caused by novel or unaccustomed exercise and results in a temporary decrease in muscle force production, a rise in passive tension, increased muscle soreness and swelling, and an increase in intramuscular proteins in blood. Consequently, EIMD can have a profound effect on the ability to perform subsequent bouts of exercise and therefore adhere to an exercise training programme. A variety of interventions have been used prophylactically and/or therapeutically in an attempt to reduce the negative effects associated with EIMD. This article focuses on some of the most commonly used strategies, including nutritional and pharmacological strategies, electrical and manual therapies and exercise. Long-term supplementation with antioxidants or β-hydroxy-β-methylbutyrate appears to provide a prophylactic effect in reducing EIMD, as does the ingestion of protein before and following exercise. Although the administration of high-dose NSAIDs may reduce EIMD and muscle soreness, it also attenuates the adaptive processes and should therefore not be prescribed for long-term treatment of EIMD. Whilst there is some evidence that stretching and massage may reduce muscle soreness, there is little evidence indicating any performance benefits. Electrical therapies and cryotherapy offer limited effect in the treatment of EIMD; however, inconsistencies in the dose and frequency of these and other interventions may account for the lack of consensus regarding their efficacy. Both as a cause and a consequence of this, there are very few evidence-based guidelines for the application of many of these interventions. Conversely, there is unequivocal evidence that prior bouts of eccentric exercise provide a protective effect against subsequent bouts of potentially damaging exercise. Further research is warranted to elucidate the most appropriate dose and frequency of interventions to attenuate EIMD and if these interventions attenuate the adaptation process. This will both clarify the efficacy of such strategies and provide guidelines for evidence-based practice.

The prevention and treatment of exercise-induced muscle damage.

Branched-chain amino acids (BCAAs) are essential amino acids that can be oxidized in skeletal muscle. It is known that BCAA oxidation is promoted by exercise. The mechanism responsible for this phenomenon is attributed to activation of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which catalyzes the second-step reaction of the BCAA catabolic pathway and is the rate-limiting enzyme in the pathway. This enzyme complex is regulated by a phosphorylation-dephosphorylation cycle. The BCKDH kinase is responsible for inactivation of the complex by phosphorylation, and the activity of the kinase is inversely correlated with the activity state of the BCKDH complex, which suggests that the kinase is the primary regulator of the complex. We found recently that administration of ligands for peroxisome proliferator-activated receptor-alpha (PPARalpha) in rats caused activation of the hepatic BCKDH complex in association with a decrease in the kinase activity, which suggests that promotion of fatty acid oxidation upregulates the BCAA catabolism. Long-chain fatty acids are ligands for PPARalpha, and the fatty acid oxidation is promoted by several physiological conditions including exercise. These findings suggest that fatty acids may be one of the regulators of BCAA catabolism and that the BCAA requirement is increased by exercise. Furthermore, BCAA supplementation before and after exercise has beneficial effects for decreasing exercise-induced muscle damage and promoting muscle-protein synthesis; this suggests the possibility that BCAAs are a useful supplement in relation to exercise and sports.

Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise

European Union Risk Assessment Report

Peroxisomal fatty acid degradation in the yeast Saccharomyces cerevisiae requires an array of β-oxidation enzyme activities as well as a set of auxiliary activities to provide the β-oxidation machinery with the proper substrates. The corresponding classical and auxiliary enzymes of β-oxidation have been completely characterized, many at the structural level with the identification of catalytic residues. Import of fatty acids from the growth medium involves passive diffusion in combination with an active, protein-mediated component that includes acyl-CoA ligases, illustrating the intimate linkage between fatty acid import and activation. The main factors involved in protein import into peroxisomes are also known, but only one peroxisomal metabolite transporter has been characterized in detail, Ant1p, which exchanges intraperoxisomal AMP with cytosolic ATP. The other known transporter is Pxa1p–Pxa2p, which bears similarity to the human adrenoleukodystrophy protein ALDP. The major players in the regulation of fatty acid-induced gene expression are Pip2p and Oaf1p, which unite to form a transcription factor that binds to oleate response elements in the promoter regions of genes encoding peroxisomal proteins. Adr1p, a transcription factor, binding upstream activating sequence 1, also regulates key genes involved in β-oxidation. The development of new, postgenomic-era tools allows for the characterization of the entire transcriptome involved in β-oxidation and will facilitate the identification of novel proteins as well as the characterization of protein families involved in this process.

The biochemistry of peroxisomal β-oxidation in the yeast Saccharomyces cerevisiae

BCAA catabolism in skeletal muscle is regulated by the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, located at the second step in the BCAA catabolic pathway. The activity of the BCKDH complex is regulated by a phosphorylation/dephosphorylation cycle. Almost all of BCKDH complex in skeletal muscle under normal and resting conditions is in an inactive/phosphorylated state, which may contribute to muscle protein synthesis and muscle growth. Exercise 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. We have examined the effects of BCAA supplementation on delayed-onset muscle soreness (DOMS) and muscle fatigue induced by squat exercise in humans. The results obtained showed that BCAA supplementation prior to squat exercise decreased DOMS and muscle fatigue occurring for a few days after exercise. These findings suggest that BCAAs may be useful for muscle recovery following exercise.

Nutraceutical Effects of Branched-Chain Amino Acids on Skeletal Muscle

The authors examined the effect of branched-chain amino acid (BCAA) supplementation on squat-exerciseinduced delayed-onset muscle soreness (DOMS) using 12 young, healthy, untrained female participants. The experiment was conducted with a crossover double-blind design. In the morning on the exercise-session day, the participants ingested either BCAA (isoleucine:leucine:valine = 1:2.3:1.2) or dextrin at 100 mg/kg body weight before the squat exercise, which consisted of 7 sets of 20 squats/set with 3-min intervals between sets. DOMS showed a peak on Days 2 and 3 in both trials, but the level of soreness was significantly lower in the BCAA trial than in the placebo. Leg-muscle force during maximal voluntary isometric contractions was measured 2 d after exercise (Day 3), and the BCAA supplementation suppressed the muscle-force decrease (to ~80% of the value recorded under the control conditions) observed in the placebo trial. Plasma BCAA concentrations, which decreased after exercise in the placebo trial, were markedly elevated during the 2 hr postexercise in the BCAA trial. Serum myoglobin concentration was increased by exercise in the placebo but not in the BCAA trial. The concentration of plasma elastase as an index of neutrophil activation appeared to increase after the squat exercise in both trials, but the change in the elastase level was significant only in the placebo trial. These results suggest that muscle damage may be suppressed by BCAA supplementation.

Branched-Chain Amino Acid Supplementation Before Squat Exercise and Delayed-Onset Muscle Soreness

Purification and partial characterization of 3-hydroxyisobutyryl-coenzyme A hydrolase of rat liver.

The effects of a diet supplemented with branched-chain amino acids (BCAA; 4.8% or 6.2%) on BCAA catabolism and glycogen metabolism in rats were examined. Rats were fed a BCAA diet or control diet for 4 wk and part of the rats were subjected to exercise training during the experimental period. Feeding the BCAA diet increased serum BCAA concentrations and activity of the hepatic branched-chain alpha-keto acid dehydrogenase complex, the rate-limiting enzyme in the catabolism of BCAA, suggesting that dietary BCAA promotes BCAA catabolism. Although the serum glucose concentration and glycogen contents in the liver and gastrocnemius muscle of rested rats were not significantly affected by feeding of the BCAA diet, those in rats exhausted by acute exercise were 2-4-fold higher in rats fed the BCAA diet than in rats fed the control diet. The activity of pyruvate dehydrogenase complex in the liver and gastrocnemius muscle after acute exercise showed reverse trends; the complex activities (especially in liver) tended to be less in the BCAA diet group than in the control diet group. These results suggest that dietary BCAA spares glycogen stores in liver and skeletal muscle during exercise and that the decrease in pyruvate dehydrogenase complex activity in these tissues by dietary BCAA is involved in the mechanisms.

Noriko Shimomura

Papers

Nutraceutical Effects of Branched-Chain Amino Acids on Skeletal Muscle

Branched-Chain Amino Acid Supplementation Before Squat Exercise and Delayed-Onset Muscle Soreness

Purification and partial characterization of 3-hydroxyisobutyryl-coenzyme A hydrolase of rat liver.

Suppression of glycogen consumption during acute exercise by dietary branched-chain amino acids in rats.