Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure.
OBJECTIVE
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.
Chatauret
Nicolas
N
Neuroscience Research Unit, University of Montreal (CHUM), Hôpital Saint-Luc, 1058 St-Denis Street, Montreal, Que., Canada H2X 3J4.
Desjardins
Paul
P
Zwingmann
Claudia
C
Rose
Christopher
C
Rao
K V Rama
KV
Butterworth
Roger F
RF
D000641:Ammonia / Q000097:blood / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000097:blood / Q000378:metabolism; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D005973:Glutamine; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase