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.
- MeSH
- adenosintrifosfát nedostatek MeSH
- chlorid uhličitý farmakologie MeSH
- jaterní cirhóza chemicky indukované komplikace metabolismus patologie MeSH
- kosterní svaly metabolismus patologie MeSH
- kyseliny ketoglutarové metabolismus MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- přijímání potravy účinky léků MeSH
- sarkopenie etiologie metabolismus patologie MeSH
- svalové proteiny metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- velikost orgánu účinky léků MeSH
- větvené aminokyseliny metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The mechanisms of cell injury resulting in a special type of cell death combining the features of apoptosis and necrosis were examined in Hep-2 cells exposed to 300 µM zinc sulfate during 24h. Acute exposure to zinc induced a rapid rise in metallothionein levels and increased oxidative stress occurring in the absence of a significant early ATP depletion. Accentuated ATP loss and elevated levels of superoxide at later treatment intervals (12h and longer) were present along with increased DNA damage. Manipulation with ATP production and inhibition of NADPH oxidase had a positive effect on zinc-related increase in oxidative stress and influenced the observed type of cell death. These results suggest that Hep-2 cells acutely exposed to zinc increase intracellular labile zinc stores and over express metalothioneins. Elevated production of peroxides in zinc-treated cells is at later treatment intervals accompanied by an increase in superoxide levels, possibly by activation of NADPH oxidase, DNA damage and severe ATP loss. Prevention of critical ATP depletion and, in particular, inhibition of oxidative stress attenuates zinc-mediated cell injury and stimulates apoptosis-like phenotype in exposed cells.
- MeSH
- adenosintrifosfát chemie nedostatek MeSH
- apoptóza genetika účinky léků MeSH
- financování vládou MeSH
- lidé MeSH
- metalothionein chemie MeSH
- NADPH-oxidasy fyziologie genetika imunologie MeSH
- nekróza etiologie genetika chemicky indukované MeSH
- oxidační stres genetika imunologie účinky léků MeSH
- poškození DNA fyziologie genetika imunologie MeSH
- zinek chemie metabolismus škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
