Muscle wasting and branched-chain amino acid, alpha-ketoglutarate, and ATP depletion in a rat model of liver cirrhosis
Abstract
The aim of the study was to examine if a rat model of liver cirrhosis induced by carbon tetrachloride (CCl4) is a suitable model of muscle wasting and alterations in amino acid and ammonia metabolism observed in cirrhotic humans. Rats were treated by intragastric gavage of CCl4 or vehicle, thrice a week, 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 plasma of cirrhotic animals.
The weights and protein contents of all muscles of CCl4-treated animals were lower when compared to controls. Increased concentrations of glutamine (GLN) and aromatic amino acids (phenylalanine and tyrosine) and decreased concentrations of branched-chain amino acids (BCAA), glutamate, alanine, and aspartate were found in plasma and muscles.
In soleus muscle, GLN increased more and glutamate and BCAA decreased less than in extensor digitorum and tibialis muscles. In muscles of cirrhotic animals increased chymotrypsin-like activity (indicates enhanced proteolysis) and decreased α-ketoglutarate and ATP levels.
ATP concentration decreased also in blood plasma. It is concluded that rat model of CCl4-induced cirrhosis is a valid model for 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 white muscles.