Glutamine synthetase in muscle is required for glutamine production during fasting and extrahepatic ammonia detoxification.

Y. He, T.B. Hakvoort, S.E. Koehler, J.L. Vermeulen, D.R. de Waart, C.C. de Theije, G.A. Ten Have, H.M. van Eijk, C. Kunne, W.T. Labruyere, S.M. Houten, M. Sokolovic, J.M. Ruijter, N.E. Deutz, W.H. Lamers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The main endogenous source of glutamine is de novo synthesis in striated muscle via the enzyme glutamine synthetase (GS). Mice in which GS is selectively, but completely eliminated from striated muscle with the Cre-loxP strategy (GS-KO/M mice) are, nevertheless, healthy and fertile. Compared to controls, the circulating concentration and net production of glutamine across the hindquarter were not different in fed GS-KO/M mice. Only a ~3-fold higher escape of ammonia revealed the absence of GS in muscle. However, after 20 hours of fasting, GS-KO/M mice were not able to mount the ~4-fold increase in glutamine production across the hindquarter that was observed in control mice. Instead, muscle ammonia production was ~5-fold higher than in control mice. The fasting-induced metabolic changes were transient and had returned to fed levels at 36 hours of fasting. Glucose consumption, and lactate and ketone-body production were similar in GS-KO/M and control mice. Challenging GS-KO/M and control mice with intravenous ammonia in stepwise increments revealed that normal muscle can detoxify ~2.5 mumol ammonia/g muscle.hour in a muscle GS-dependent manner, with simultaneous accumulation of urea, whereas GS-KO/M mice responded with accumulation of glutamine and other amino acids, but not urea. These findings demonstrate that GS in muscle is dispensable in fed mice, but plays a key role in mounting the adaptive response to fasting by transiently facilitating the production of glutamine. Furthermore, muscle GS contributes to ammonia detoxification and urea synthesis. These functions are apparently not vital as long as other organs function normally.
Original languageEnglish
Pages (from-to)9516-9524
Number of pages9
JournalJournal of Biological Chemistry
Issue number13
Publication statusPublished - 26 Mar 2010


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