Holeček Milan, Vodeničarovová Melita
Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic.
Int J Exp Pathol. 2018 Dec;99(6):274-281. doi: 10.1111/iep.12299. Epub 2019 Jan 13.
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.
本研究的目的是检验四氯化碳（CCl4）诱导的肝硬化大鼠模型是否是肝硬化患者肌肉萎缩和氨基酸代谢改变的合适模型。大鼠通过灌胃给予CCl4或赋形剂，持续45天。在研究结束时分析血浆以及不同类型的肌肉——胫前肌（主要为白肌纤维）、比目鱼肌（红肌）和趾长伸肌（白肌）。在肝硬化动物的血浆中发现了肝功能受损的特征性生物标志物。与对照组相比，CCl4处理动物的所有肌肉重量和蛋白质含量均较低。在血浆和肌肉中发现谷氨酰胺（GLN）和芳香族氨基酸（苯丙氨酸和酪氨酸）浓度升高，而支链氨基酸（BCAA）、谷氨酸（GLU）、丙氨酸和天冬氨酸浓度降低。在比目鱼肌中，GLN的增加幅度和GLU及BCAA的降低幅度均大于趾长伸肌和胫前肌。在肝硬化动物的肌肉中发现胰凝乳蛋白酶样活性增加（表明蛋白水解增强），α-酮戊二酸和ATP水平降低。血浆中的ATP浓度也降低。得出的结论是，CCl4诱导的肝硬化大鼠模型是研究肝性恶病质的有效模型，该模型所呈现的改变符合氨在肝硬化患者BCAA消耗、柠檬酸循环和线粒体功能障碍以及肌肉萎缩发病机制中作用的理论。研究结果表明，红色肌肉对氨的解毒作用比对白色肌肉更有效，可将氨转化为GLN。
