Most cited article - PubMed ID 28493406
Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions
The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased.
- Keywords
- branched-chain amino acids, glycine, insulin resistance, serine,
- MeSH
- Amino Acids metabolism MeSH
- Diabetes Mellitus, Type 2 * metabolism MeSH
- Glycine metabolism MeSH
- Glycolysis MeSH
- Pyruvic Acid MeSH
- Humans MeSH
- Serine metabolism MeSH
- Amino Acids, Branched-Chain metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Amino Acids MeSH
- Glycine MeSH
- Pyruvic Acid MeSH
- Serine MeSH
- Amino Acids, Branched-Chain MeSH
The aim of the article is to examine side effects of increased dietary intake of amino acids, which are commonly used as a dietary supplement. In addition to toxicity, mutagenicity and carcinogenicity, attention is focused on renal and gastrointestinal tract functions, ammonia production, and consequences of a competition with other amino acids for a carrier at the cell membranes and enzymes responsible for their degradation. In alphabetic order are examined arginine, beta-alanine, branched-chain amino acids, carnosine, citrulline, creatine, glutamine, histidine, beta -hydroxy- beta -methylbutyrate, leucine, and tryptophan. In the article is shown that enhanced intake of most amino acid supplements may not be risk-free and can cause a number of detrimental side effects. Further research is necessary to elucidate effects of high doses and long-term consumption of amino acid supplements on immune system, brain function, muscle protein balance, synthesis of toxic metabolites, and tumor growth and examine their suitability under certain circumstances. These include elderly, childhood, pregnancy, nursing a baby, and medical condition, such as diabetes and liver disease. Studies are also needed to examine adaptive response to a long-term intake of any substance and consequences of discontinuation of supplementation.
- MeSH
- Amino Acids adverse effects metabolism MeSH
- Arginine pharmacology MeSH
- Child MeSH
- Glutamine * metabolism pharmacology MeSH
- Histidine metabolism MeSH
- Muscle, Skeletal metabolism MeSH
- Humans MeSH
- Dietary Supplements * adverse effects MeSH
- Aged MeSH
- Pregnancy MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Aged MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Amino Acids MeSH
- Arginine MeSH
- Glutamine * MeSH
- Histidine MeSH
Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.
- Keywords
- ATP depletion, branched-chain amino acids, ketoglutarate, muscles, serine,
- MeSH
- Amino Acids administration & dosage pharmacology MeSH
- Diabetes Mellitus, Type 1 chemically induced drug therapy metabolism MeSH
- Injections, Intraperitoneal MeSH
- Injections, Subcutaneous MeSH
- Liver drug effects metabolism MeSH
- Muscle, Skeletal drug effects metabolism MeSH
- Rats MeSH
- Rats, Wistar MeSH
- Streptozocin administration & dosage MeSH
- Valerates administration & dosage pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amino Acids MeSH
- beta-hydroxyisovaleric acid MeSH Browser
- Streptozocin MeSH
- Valerates MeSH
In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements. It is hypothesized that, under hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions.
- Keywords
- exercise, glutamine, liver cirrhosis, urea-cycle disorders, α-ketoglutarate,
- Publication type
- Journal Article MeSH
- Review MeSH
Both regular exercise training and beta-hydroxy-beta-methylbutyrate (HMB) supplementation are shown as effective treatments to delay or reverse frailty and reduce cognitive impairment in older people. However, there is very little evidence on the true benefits of combining both strategies. The aim of this meta-analysis was to quantify the effects of exercise in addition to HMB supplementation, on physical and cognitive health in older adults. Data from 10 randomized controlled trials (RCTs) investigating the effect of HMB supplementation and physical function in adults aged 50 years or older were analyzed, involving 384 participants. Results showed that HMB supplementation in addition to physical exercise has no or fairly low impact in improving body composition, muscle strength, or physical performance in adults aged 50 to 80 years, compared to exercise alone. There is a gap of knowledge on the beneficial effects of HMB combined with exercise to preserve cognitive functions in aging and age-related neurodegenerative diseases. Future RCTs are needed to refine treatment choices combining HMB and exercises for older people in particular populations, ages, and health status. Specifically, interventions in older adults aged 80 years or older, with cognitive impairment, frailty, or limited mobility are required.
- Keywords
- elderly, leucine, neuromuscular function, nutrition, resistance training, sarcopenia,
- MeSH
- Exercise physiology MeSH
- Humans MeSH
- Dietary Supplements * MeSH
- Aging * MeSH
- Valerates administration & dosage pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
- Names of Substances
- beta-hydroxyisovaleric acid MeSH Browser
- Valerates MeSH
Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. We examined the effects of an HMB-enriched diet in healthy rats and rats with liver cirrhosis induced by multiple doses of carbon tetrachloride (CCl4). HMB increased branched-chain amino acids (BCAAs; valine, leucine and isoleucine) in blood and BCAA and ATP in muscles of healthy animals. The effect on muscle mass and protein content was insignificant. In CCl4-treated animals alterations characteristic of liver cirrhosis were found with decreased ratio of the BCAA to aromatic amino acids in blood and lower muscle mass and ATP content when compared with controls. In CCl4-treated animals consuming HMB, we observed higher mortality, lower body weight, higher BCAA levels in blood plasma, higher ATP content in muscles, and lower ATP content and higher cathepsin B and L activities in the liver when compared with CCl4-treated animals without HMB. We conclude that (1) HMB supplementation has a positive effect on muscle mitochondrial function and enhances BCAA concentrations in healthy animals and (2) the effects of HMB on the course of liver cirrhosis in CCl4-treated rats are detrimental. Further studies examining the effects of HMB in other models of hepatic injury are needed to determine pros and cons of HMB in the treatment of subjects with liver cirrhosis.
- Keywords
- branched-chain amino acids, hepatic cachexia, insulin resistance, leucine, liver cirrhosis,
- MeSH
- Carbon Tetrachloride metabolism MeSH
- Liver Cirrhosis metabolism MeSH
- Liver drug effects metabolism MeSH
- Muscle, Skeletal drug effects metabolism MeSH
- Leucine metabolism MeSH
- Rats, Wistar MeSH
- Dietary Supplements MeSH
- Valerates pharmacology MeSH
- Amino Acids, Branched-Chain metabolism MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- beta-hydroxyisovaleric acid MeSH Browser
- Carbon Tetrachloride MeSH
- Leucine MeSH
- Valerates MeSH
- Amino Acids, Branched-Chain MeSH
Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.
