Studies from the last decades indicate that increased levels of ammonia contribute to muscle wasting in critically ill patients. The aim of the article is to examine the effects of two different causes of hyperammonemia-increased ATP degradation in muscles during strenuous exercise and impaired ammonia detoxification to urea due to liver cirrhosis. During exercise, glycolysis, citric acid cycle (CAC) activity, and ATP synthesis in muscles increase. In cirrhosis, due to insulin resistance and mitochondrial dysfunction, glycolysis, CAC activity, and ATP synthesis in muscles are impaired. Both during exercise and in liver cirrhosis, there is increased ammonia detoxification to glutamine (Glu + NH3 + ATP → Gln + ADP + Pi), increased drain of ketoglutarate (α-KG) from CAC for glutamate synthesis by α-KG-linked aminotransferases, glutamate, aspartate, and α-KG deficiency, increased oxidation of branched-chain amino acids (BCAA; valine, leucine, and isoleucine), and protein-energy wasting in muscles. It is concluded that ammonia can contribute to muscle wasting regardless of the cause of its increased levels and that similar strategies can be designed to increase muscle performance in athletes and reduce muscle loss in patients with hyperammonemia. The pros and cons of glutamate, α-KG, aspartate, BCAA, and branched-chain keto acid supplementation are discussed.

• Keywords
• branched-chain amino acids, glutamic acid, glutamine, hyperammonemia,
• Publication type
• Journal Article MeSH
• Review MeSH

The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to alpha-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (alpha-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.

• MeSH
• Diabetes Mellitus metabolism   MeSH
• Isoleucine metabolism   MeSH
• Liver Cirrhosis metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Leucine metabolism   MeSH
• Humans MeSH
• Metabolic Diseases metabolism   MeSH
• Valine metabolism   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Isoleucine MeSH
• Leucine MeSH
• Valine MeSH
• Amino Acids, Branched-Chain 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

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

The aim of the study was to examine whether a rat model of liver cirrhosis induced by carbon tetrachloride (CCl4) is a suitable model of muscle wasting and alterations in amino acid metabolism in cirrhotic humans. Rats were treated by intragastric gavage of CCl4 or vehicle for 45 days. Blood plasma and different muscle types-tibialis anterior (mostly white fibres), soleus (red muscle) and extensor digitorum longus (white muscle) - were analysed at the end of the study. Characteristic biomarkers of impaired hepatic function were found in the plasma of cirrhotic animals. The weights and protein contents of all muscles of CCl4-treated animals were lower when compared with controls. Increased concentrations of glutamine (GLN) and aromatic amino acids (phenylalanine and tyrosine) and decreased concentrations of branched-chain amino acids (BCAA), glutamate (GLU), alanine and aspartate were found in plasma and muscles. In the soleus muscle, GLN increased more and GLU and BCAA decreased less than in the extensor digitorum and tibialis muscles. Increased chymotrypsin-like activity (indicating enhanced proteolysis) and decreased α-ketoglutarate and ATP levels were found in muscles of cirrhotic animals. ATP concentration also decreased in blood plasma. It is concluded that a rat model of CCl4-induced cirrhosis is a valid model for the investigation of hepatic cachexia that exhibits alterations in line with a theory of role of ammonia in pathogenesis of BCAA depletion, citric cycle and mitochondria dysfunction, and muscle wasting in cirrhotic subjects. The findings indicate more effective ammonia detoxification to GLN in red than in white muscles.

• Keywords
• ammonia detoxification, cachexia, glutamine, liver cirrhosis,
• MeSH
• Adenosine Triphosphate deficiency   MeSH
• Carbon Tetrachloride pharmacology   MeSH
• Liver Cirrhosis chemically induced   complications   metabolism   pathology   MeSH
• Muscle, Skeletal metabolism   pathology   MeSH
• Ketoglutaric Acids metabolism   MeSH
• Disease Models, Animal MeSH
• Rats, Wistar MeSH
• Eating drug effects   MeSH
• Sarcopenia etiology   metabolism   pathology   MeSH
• Muscle Proteins metabolism   MeSH
• Body Weight drug effects   MeSH
• Organ Size drug effects   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Carbon Tetrachloride MeSH
• Ketoglutaric Acids MeSH
• Muscle Proteins 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.

• Keywords
• Ammonia, Cachexia, Cirrhosis, Diabetes, Glutamine, Nutrition,
• Publication type
• Journal Article MeSH
• Review MeSH

There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.

• MeSH
• Ammonia metabolism   MeSH
• Enterocytes metabolism   MeSH
• Phenylbutyrates adverse effects   pharmacology   therapeutic use   MeSH
• Glutamine metabolism   MeSH
• Glutaminase antagonists & inhibitors   MeSH
• Hyperammonemia drug therapy   etiology   metabolism   MeSH
• Hepatic Encephalopathy diet therapy   drug therapy   metabolism   MeSH
• Liver metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Critical Illness MeSH
• Glutamic Acid metabolism   pharmacology   therapeutic use   MeSH
• Ketoglutaric Acids adverse effects   pharmacology   therapeutic use   MeSH
• Kidney metabolism   MeSH
• Drug Interactions MeSH
• Humans MeSH
• Microbiota MeSH
• Brain metabolism   MeSH
• Organ Specificity MeSH
• Intestines microbiology   MeSH
• Amino Acids, Branched-Chain metabolism   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Ammonia MeSH
• Phenylbutyrates MeSH
• Glutamine MeSH
• Glutaminase MeSH
• Glutamic Acid MeSH
• Ketoglutaric Acids MeSH
• Amino Acids, Branched-Chain MeSH

Muscle wasting is a serious complication of various clinical conditions that significantly worsens the prognosis of the illnesses. Clinically relevant models of muscle wasting are essential for understanding its pathogenesis and for selective preclinical testing of potential therapeutic agents. The data presented here indicate that muscle wasting has been well characterized in rat models of sepsis (endotoxaemia, and caecal ligation and puncture), in rat models of chronic renal failure (partial nephrectomy), in animal models of intensive care unit patients (corticosteroid treatment combined with peripheral denervation or with administration of neuromuscular blocking drugs) and in murine and rat models of cancer (tumour cell transplantation). There is a need to explore genetically engineered mouse models of cancer. The degree of protein degradation in skeletal muscle is not well characterized in animal models of liver cirrhosis, chronic heart failure and chronic obstructive pulmonary disease. The major difficulties with all models are standardization and high variation in disease progression and a lack of reflection of clinical reality in some of the models. The translation of the information obtained by using these models to clinical practice may be problematic.

• MeSH
• Muscle, Skeletal metabolism   pathology   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Neoplasms complications   metabolism   pathology   MeSH
• Proteolysis MeSH
• Sepsis complications   metabolism   pathology   MeSH
• Muscular Atrophy etiology   metabolism   pathology   MeSH
• Wasting Syndrome etiology   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH