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.

Department of Physiology Faculty of Medicine in Hradec Kralove Charles University Czech Republic

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Dasarathy S, Merli M. Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol. 2016;65:1232‐1244. PubMed PMC

Hanai T, Shiraki M, Ohnishi S, et al. Rapid skeletal muscle wasting predicts worse survival in patients with liver cirrhosis. Hepatol Res. 2016;46:743‐751. PubMed

Nardelli S, Lattanzi B, Torrisi S, et al. Sarcopenia is risk factor for development of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt placement. Clin Gastroenterol Hepatol. 2017;15:934‐936. PubMed

Peng S, Plank LD, McCall JL, et al. Body composition, muscle function, and energy expenditure in patients with liver cirrhosis: a comprehensive study. Am J Clin Nutr. 2007;85:1257‐1266. PubMed

Ng EH, Lowry SF. Nutritional support and cancer cachexia. Hematol Oncol Clin North Am. 1991;5:161‐194. PubMed

Shaw JHF, Wolfe RR. An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients: Studies in the basal state and the response to total parenteral nutrition. Ann Surg. 1989;209:63‐72. PubMed PMC

Streate SJ, Beddoe AH, Hill GL. Aggressive nutritional support does not prevent protein loss despite fat gain in septic intensive care patients. J Trauma. 1987;27:262‐266. PubMed

Blondé‐Cynober F, Plassart F, Rey C, et al. Assessment of the carbon tetrachloride‐induced cirrhosis model for studies of nitrogen metabolism in chronic liver disease. Ann Nutr Metab. 1994;38:238‐248. PubMed

Holecek M, Skopec F, Sprongl L. Protein metabolism in cirrhotic rats: effect of dietary restriction. Ann Nutr Metab. 1995;39:346‐354. PubMed

Schott K, Poetter U, Neuhoff V. Ammonia inhibits protein synthesis in slices from young rat brain. J Neurochem. 1984;42:644‐646. PubMed

Holecek M, Sprongl L, Tichy M. Effect of hyperammonemia on leucine and protein metabolism in rats. Metabolism Clin Exp. 2000;49:1330‐1334. PubMed

Holecek M, Kandar R, Sispera L, et al. Acute hyperammonemia activates branched‐chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle. Amino Acids. 2011;40:575‐584. PubMed

Holeček M, Vodeničarovová M. Effects of branched‐chain amino acids on muscles under hyperammonemic conditions. J Physiol Biochem. 2018;74:523‐530. PubMed

Leweling H, Breitkreutz R, Behne F, et al. Hyperammonemia‐induced depletion of glutamate and branched‐chain amino acids in muscle and plasma. J Hepatol. 1996;25:756‐762. PubMed

Davuluri G, Allawy A, Thapaliya S, et al. Hyperammonaemia‐induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J Physiol. 2016a;594:7341‐7360. PubMed PMC

Wagenmakers AJ, Coakley JH, Edwards RH. Metabolism of branched‐chain amino acids and ammonia during exercise: clues from McArdle‘s disease. Int J Sports Med. 1990;11(Suppl. 2):S101‐S113. PubMed

Holecek M, Mraz J, Tilser I. Plasma amino acids in four models of experimental liver injury in rats. Amino Acids. 1996a;10:229‐241. PubMed

Holecek M, Tilser I, Skopec F, et al. Leucine metabolism in rats with cirrhosis. J Hepatol. 1996b;24:209‐216. PubMed

Rubin E, Popper H. The evolution of human cirrhosis deduced from observations in experimental animals. Medicine (Baltimore). 1967;46:163‐183. PubMed

Bosoi CR, Oliveira MM, Ochoa‐Sanchez R, et al. The bile duct ligated rat: a relevant model to study muscle mass loss in cirrhosis. Metab Brain Dis. 2017;32:513‐518. PubMed

Holeček M, Mičuda S. Amino acid concentrations and protein metabolism of two types of rat skeletal muscle in postprandial state and after brief starvation. Physiol Res. 2017;66:959‐967. PubMed

Kadlcikova J, Holecek M, Safranek R, et al. Effects of proteasome inhibitors MG132, ZL3VS and AdaAhx3L3VS on protein metabolism in septic rats. Int J Exp Pathol. 2004;85:365‐371. PubMed PMC

Gomes‐Marcondes MC, Tisdale MJ. Induction of protein catabolism and the ubiquitin‐proteasome pathway by mild oxidative stress. Cancer Lett. 2002;180:69‐74. PubMed

Koohmaraie M, Kretchmar DH. Comparisons of four methods for quantification of lysosomal cysteine proteinase activities. J Anim Sci. 1990;68:2362‐2370. PubMed

Campollo O, Sprengers D, Dam G, et al. Protein tolerance to standard and high protein meals in patients with liver cirrhosis. World J. Hepatol. 2017;9:667‐676. PubMed PMC

Dam G, Sørensen M, Buhl M, et al. Muscle metabolism and whole blood amino acid profile in patients with liver disease. Scand J Clin Lab Invest. 2015;75:674‐680. PubMed

Holecek M, Skalská H, Mráz J. Plasma amino acid levels after carbon tetrachloride induced acute liver damage. A dose‐response and time‐response study in rats. Amino Acids. 1999;16:1‐11. PubMed

Holeček M. Branched‐chain amino acid supplementation in treatment of liver cirrhosis: updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation. Nutrition. 2017;41:80‐85. PubMed

Plauth M, Schütz T. Branched‐chain amino acids in liver disease: new aspects of long known phenomena. Curr Opin Clin Nutr Metab Care. 2011;14:61‐66. PubMed

Giusto M, Barberi L, Di Sario F, et al. Skeletal muscle myopenia in mice model of bile duct ligation and carbon tetrachloride‐induced liver cirrhosis. Physiol Rep. 2017;5(7):e13153. PubMed PMC

Weber FL, Macechko PT, Kelson SR, et al. Increased muscle protein catabolism caused by carbon tetrachloride hepatic injury in rats. Gastroenterology. 1992;102:1700‐1706. PubMed

Iob V, Coon WW, Sloan M. Free amino acids in liver, plasma, and muscle of patients with cirrhosis of the liver. J Surg Res. 1967;7:41‐43. PubMed

Plauth M, Egberts EH, Abele R, et al. Characteristic pattern of free amino acids in plasma and skeletal muscle in stable hepatic cirrhosis. Hepatogastroenterology. 1990;37:135‐139. PubMed

Montanari A, Simoni I, Vallisa D, et al. Free amino acids in plasma and skeletal muscle of patients with liver cirrhosis. Hepatology. 1988;8:1034‐1039. PubMed

Honda T, Fukuda Y, Nakano I, et al. Effects of liver failure on branched‐chain alpha‐keto acid dehydrogenase complex in rat liver and muscle: comparison between acute and chronic liver failure. J Hepatol. 2004;40:439‐445. PubMed

Schauder P, Schröder K, Herbertz L, et al. Evidence for valine intolerance in patients with cirrhosis. Hepatology. 1984;4:667‐670. PubMed

Möller P, Bergström J, Fürst P, et al. Muscle biopsy studies in patients with moderate liver cirrhosis with special reference to energy‐rich phosphagens and electrolytes. Scand J Gastroenterol. 1984;19:267‐272. PubMed

Davuluri G, Krokowski D, Guan BJ, et al. Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l‐leucine in cirrhosis. J Hepatol. 2016b;65:929‐937. PubMed PMC

Hernández‐Muñoz R, Glender W, Díaz‐Muñoz M, et al. Alterations of ATP levels and of energy parameters in the blood of alcoholic and nonalcoholic patients with liver damage. Alcohol Clin Exp Res. 1991;15:500‐503. PubMed

Yang Q, Birkhahn RH. Branched‐chain transaminase and keto acid dehydrogenase activities in burned rats: evidence for a differential adaptation according to sex. Nutrition. 1997;13:640‐645. PubMed

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