Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure

Nicolas Chatauret, Paul Desjardins, Claudia Zwingmann, Christopher Rose, K. V.Rama Rao, Roger F. Butterworth

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Background/Aims: It has been proposed that, in acute liver failure, skeletal muscle adapts to become the principle organ responsible for removal of blood-borne ammonia by increasing glutamine synthesis, a reaction that is catalyzed by the cytosolic ATP-dependent enzyme glutamine synthetase. To address this issue, glutamine synthetase expression and activities were measured in skeletal muscle of rats with acute liver failure resulting from hepatic devascularization. Methods: Glutamine synthetase protein and gene expression were investigated using immunoblotting and semi-quantitative RT-PCR analysis. Glutamine synthetase activity and glutamine de novo synthesis were measured using, respectively, a standard enzymatic assay and [13C]-nuclear magnetic resonance spectroscopy. Results: Glutamine synthetase protein (but not gene) expression and enzyme activities were significantly up-regulated leading to increased de novo synthesis of glutamine and increased skeletal muscle capacity for ammonia removal in acute liver failure. In contrast to skeletal muscle, expression and activities of glutamine synthetase in the brain were significantly decreased. Conclusions: These findings demonstrate that skeletal muscle adapts, through a rapid induction of glutamine synthetase, to increase its capacity for removal of blood-borne ammonia in acute liver failure. Maintenance of muscle mass together with the development of agents with the capacity to stimulate muscle glutamine synthetase could provide effective ammonia-lowering strategies in this disorder.

Original languageEnglish (US)
Pages (from-to)1083-1088
Number of pages6
JournalJournal of Hepatology
Volume44
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology

Keywords

  • Acute liver failure
  • Ammonia
  • Brain edema
  • Glutamine
  • Glutamine synthetase
  • Nuclear magnetic resonance spectroscopy
  • Skeletal muscle

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