Hyperammonemia is considered to be the main cause of decreased levels of the branched-chain amino acids (BCAA), valine, leucine, and isoleucine, in liver cirrhosis. In this study we investigated whether the decrease in BCAA is caused by the direct effect of ammonia on BCAA metabolism and the effect of ammonia on BCAA and protein metabolism in different types of skeletal muscle. M. soleus (SOL, slow-twitch, red muscle) and m. extensor digitorum longus (EDL, fast-twitch, white muscle) of white rat were isolated and incubated in a medium with or without 500 μM ammonia. We measured the exchange of amino acids between the muscle and the medium, amino acid concentrations in the muscle, release of branched-chain keto acids (BCKA), leucine oxidation, total and myofibrillar proteolysis, and protein synthesis. Hyperammonemia inhibited the BCAA release (81% in SOL and 60% in EDL vs. controls), increased the release of BCKA (133% in SOL and 161% in EDL vs. controls) and glutamine (138% in SOL and 145% in EDL vs. controls), and increased the leucine oxidation in EDL (174% of controls). Ammonia also induced a significant increase in glutamine concentration in skeletal muscle. The effect of ammonia on intracellular BCAA concentration, protein synthesis and on total and myofibrillar proteolysis was insignificant. The data indicates that hyperammonemia directly affects the BCAA metabolism in skeletal muscle which results in decreased levels of BCAA in the extracellular fluid. The effect is associated with activated synthesis of glutamine, increased BCAA oxidation, decreased release of BCAA, and enhanced release of BCKA. These metabolic changes are not directly associated with marked changes in protein turnover. The effect of ammonia is more pronounced in muscles with high content of white fibres.

• MeSH
• akutní nemoc MeSH
• amoniak krev   metabolismus   MeSH
• extracelulární prostor metabolismus   MeSH
• hyperamonemie komplikace   metabolismus   MeSH
• jaterní cirhóza etiologie   metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar MeSH
• větvené aminokyseliny krev   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amoniak MeSH
• větvené aminokyseliny MeSH

The cause of muscle wasting and decreased plasma levels of branched chain amino acids (BCAA), valine, leucine, and isoleucine in liver cirrhosis is obscure. Here we have evaluated the effect of hyperammonemia. Rats were infused with either an ammonium acetate/bicarbonate mixture, a sodium acetate/bicarbonate mixture, or saline for 320 minutes. The parameters of leucine and protein metabolism were evaluated in the whole body and in several tissues using a primed constant intravenous infusion of L-[1-14C]leucine. Ammonium infusion caused an increase in ammonia and glutamine levels in plasma, a decrease in BCAA and alanine in plasma and skeletal muscle, a significant decrease in whole-body proteolysis and protein synthesis, and an increase in leucine oxidized fraction. A significant decrease in protein synthesis after ammonium infusion was observed in skeletal muscle while a nonsignificant effect was observed in liver, gut, heart, spleen, and kidneys. We conclude that the decrease in plasma BCAA after ammonia infusion is associated with decreased proteolysis and increased leucine oxidized fraction.

• MeSH
• amoniak krev   MeSH
• krysa rodu Rattus MeSH
• leucin metabolismus   MeSH
• potkani Wistar MeSH
• proteiny metabolismus   MeSH
• větvené aminokyseliny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amoniak MeSH
• leucin MeSH
• proteiny MeSH
• větvené aminokyseliny MeSH

Na(+)-dependent binding of L-glutamate in cortical and hippocampal synaptic membranes from hyperammonemic rats was compared to corresponding data in the controls. In hippocampal membranes, repeated hyperammonemia resulted in a 13% and 18% decrease in binding in 20-day-old and 50-day-old rats, respectively. The decrease was statistically significant (P < 0.05) in the older animals and Scatchard analysis revealed a 19% reduction in the number of binding sites without any changes in the affinity. Within the hippocampal formation, the binding in the dentate gyrus was the most sensitive to hyperammonemia where a 21% decrease was found (P < 0.01), whilst the decline of binding in CA1 and CA3 areas of the hippocampus proper was not significant. The results support the idea that excessive accumulation of extracellular glutamate during hyperammonemia is a consequence not only of its increased release, but also of the blocking of Na(+)-dependent binding of glutamate to specific uptake sites.

• MeSH
• amoniak krev   MeSH
• glutamátové receptory účinky léků   metabolismus   MeSH
• glutamáty metabolismus   MeSH
• hipokampus metabolismus   ultrastruktura   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• kyselina glutamová MeSH
• mozek - chemie fyziologie   MeSH
• mozková kůra metabolismus   ultrastruktura   MeSH
• sodík fyziologie   MeSH
• stárnutí metabolismus   MeSH
• synaptické membrány metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amoniak MeSH
• glutamátové receptory MeSH
• glutamáty MeSH
• kyselina glutamová MeSH
• sodík MeSH

Gills of fish are involved in respiration, excretion and osmoregulation. Due to numerous interactions between these processes, branchial diseases have serious implications on fish health. Here, "koi sleepy disease" (KSD), caused by carp edema virus (CEV) infection was used to study physiological, immunological and metabolic consequences of a gill disease in fish. A metabolome analysis shows that the moderately hypoxic-tolerant carp can compensate the respiratory compromise related to this infection by various adaptations in their metabolism. Instead, the disease is accompanied by a massive disturbance of the osmotic balance with hyponatremia as low as 71.65 mmol L-1, and an accumulation of ammonia in circulatory blood causing a hyperammonemia as high as 1123.24 µmol L-1. At water conditions with increased ambient salt, the hydro-mineral balance and the ammonia excretion were restored. Importantly, both hyponatremia and hyperammonemia in KSD-affected carp can be linked to an immunosuppression leading to a four-fold drop in the number of white blood cells, and significant downregulation of cd4, tcr a2 and igm expression in gills, which can be evaded by increasing the ion concentration in water. This shows that the complex host-pathogen interactions within the gills can have immunosuppressive consequences, which have not previously been addressed in fish. Furthermore, it makes the CEV infection of carp a powerful model for studying interdependent pathological and immunological effects of a branchial disease in fish.

• Klíčová slova
• Carp edema virus, gills, hyperammonemia, hyponatremia, immunosuppression, koi sleepy disease, metabolome, osmoregulation,
• MeSH
• amoniak MeSH
• edém MeSH
• hyperamonemie * veterinární   MeSH
• hyponatremie * veterinární   MeSH
• infekce vyvolané poxviry * imunologie   veterinární   MeSH
• kapři * imunologie   virologie   MeSH
• nemoci ryb * imunologie   virologie   MeSH
• Poxviridae MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amoniak MeSH

The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf ash mouse model carries a variant (c.386G>A, p.Arg129His) that is also found in patients. Male spf ash mice have a mild biochemical phenotype with low OTC activity (5%-10% of wild-type), resulting in elevated urinary orotic acid but no hyperammonemia. We recently established a dried blood spot method for in vivo quantification of ureagenesis by Gas chromatography-mass spectrometry (GC-MS) using stable isotopes. Here, we applied this assay to wild-type and spf ash mice to assess ureagenesis at different ages. Unexpectedly, we found an age-dependency with a higher capacity for ammonia detoxification in young mice after weaning. A parallel pattern was observed for carbamoylphosphate synthetase 1 and OTC enzyme expression and activities, which may act as pacemaker of this ammonia detoxification pathway. Moreover, high ureagenesis in younger mice was accompanied by elevated periportal expression of hepatic glutamine synthetase, another main enzyme required for ammonia detoxification. These observations led us to perform a more extensive analysis of the spf ash mouse in comparison to the wild-type, including characterization of the corresponding metabolites, enzyme activities in the liver and plasma and the gut microbiota. In conclusion, the comprehensive enzymatic and metabolic analysis of ureagenesis performed in the presented depth was only possible in animals. Our findings suggest such analyses being essential when using the mouse as a model and revealed age-dependent activity of ammonia detoxification.

• Klíčová slova
• age-dependency, gut microbiome, hyperammonemia, ornithine transcarbamylase (OTC) deficiency, spfash mouse model, urea cycle disorders, ureagenesis,
• MeSH
• amoniak metabolismus   MeSH
• hyperamonemie genetika   metabolismus   patologie   MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• močovina metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• myši MeSH
• nemoc z nedostatku ornithinkarbamoyltransferázy genetika   metabolismus   patologie   MeSH
• ornithinkarbamoyltransferasa genetika   MeSH
• stárnutí fyziologie   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• amoniak MeSH
• močovina MeSH
• ornithinkarbamoyltransferasa MeSH

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

• Klíčová slova
• carbamoyl phosphate synthetase 1, citrulline, liver transplantation, ornithine transcarbamylase, substitution, urea cycle disorders,
• MeSH
• amoniak metabolismus   MeSH
• arginin terapeutické užití   MeSH
• citrulin MeSH
• hyperamonemie * farmakoterapie   MeSH
• karbamoylfosfát metabolismus   terapeutické užití   MeSH
• karbamoylfosfátsynthasa (amoniak) metabolismus   MeSH
• lidé MeSH
• nemoc z nedostatku ornithinkarbamoyltransferázy * chirurgie   MeSH
• ornithinkarbamoyltransferasa MeSH
• retrospektivní studie MeSH
• transplantace jater * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amoniak MeSH
• arginin MeSH
• citrulin MeSH
• karbamoylfosfát MeSH
• karbamoylfosfátsynthasa (amoniak) MeSH
• ornithinkarbamoyltransferasa MeSH

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.

• Klíčová slova
• branched-chain amino acids, glutamic acid, glutamine, hyperammonemia,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Typically, mammalian and avian models have been used to examine the effects of ammonia on skeletal muscle. Hyperammonemia causes sarcopenia or muscle wasting, in mammals and has been linked to sarcopenia in liver disease patients. Avian models of skeletal muscle have responded positively to hyperammonemia, differing from the mammalian response. Fish skeletal muscle has not been examined as extensively as mammalian and avian muscle. Fish skeletal muscle shares similarities with avian and mammalian muscle but has notable differences in growth, fiber distribution, and response to the environment. The wide array of body sizes and locomotion needs of fish also leads to greater diversity in muscle fiber distribution and growth between different fish species. The response of fish muscle to high levels of ammonia is important for aquaculture and quality food production but has not been extensively studied to date. Understanding the differences between fish, mammalian and avian species' myogenic response to hyperammonemia could lead to new therapies for muscle wasting due to a greater understanding of the mechanisms behind skeletal muscle regulation and how ammonia effects these mechanisms. This paper provides an overview of fish skeletal muscle and ammonia excretion and toxicity in fish, as well as a comparison to avian and mammalian species.

• Klíčová slova
• ammonia, avian, fish, mammal, muscle, myostatin,
• MeSH
• amoniak farmakologie   toxicita   MeSH
• hyperamonemie etiologie   MeSH
• jaterní cirhóza etiologie   MeSH
• kosterní svalová vlákna účinky léků   MeSH
• kosterní svaly účinky léků   metabolismus   MeSH
• ptáci MeSH
• ryby MeSH
• sarkopenie etiologie   MeSH
• savci MeSH
• svalová atrofie metabolismus   patofyziologie   MeSH
• vývoj svalů účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• amoniak MeSH

• MeSH
• amoniak krev   MeSH
• kojenec MeSH
• lidé MeSH
• nemoci nervového systému krev   diagnóza   MeSH
• novorozenec MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• amoniak MeSH

The article explains the pathogenesis of disturbances in branched-chain amino acid (BCAA; valine, leucine, and isoleucine) and protein metabolism in various forms of hepatic injury and it is suggested that the main cause of decrease in plasma BCAA concentration in liver cirrhosis is hyperammonemia. Three possible targets of BCAA supplementation in hepatic disease are suggested: (1) hepatic encephalopathy, (2) liver regeneration, and (3) hepatic cachexia. The BCAA may ameliorate hepatic encephalopathy by promoting ammonia detoxification, correction of the plasma amino acid imbalance, and by reduced brain influx of aromatic amino acids. The influence of BCAA supplementation on hepatic encephalopathy could be more effective in chronic hepatic injury with hyperammonemia and low concentrations of BCAA in blood than in acute hepatic illness, where hyperaminoacidemia frequently develops. The favorable effect of BCAA on liver regeneration and nutritional state of the body is related to their stimulatory effect on protein synthesis, secretion of hepatocyte growth factor, glutamine production and inhibitory effect on proteolysis. Presumably the beneficial effect of BCAA on hepatic cachexia is significant in compensated liver disease with decreased plasma BCAA concentrations, whereas it is less pronounced in hepatic diseases with inflammatory complications and enhanced protein turnover. It is concluded that specific benefits associated with BCAA supplementation depend significantly on the type of liver disease and on the presence of inflammatory reaction. An important task for clinical research is to identify groups of patients for whom BCAA treatment can significantly improve the health-related quality of life and the prognosis of hepatic disease.

• MeSH
• hyperamonemie krev   farmakoterapie   MeSH
• jaterní encefalopatie farmakoterapie   MeSH
• kachexie farmakoterapie   etiologie   MeSH
• lidé MeSH
• nemoci jater krev   komplikace   farmakoterapie   MeSH
• potravní doplňky MeSH
• regenerace jater MeSH
• větvené aminokyseliny aplikace a dávkování   krev   nedostatek   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• větvené aminokyseliny MeSH