title: Glutamine synthetase in muscle is required for glutamine production during fasting and extrahepatic ammonia detoxification.
abstract: The main endogenous source of glutamine is de novo synthesis in striated muscle via the enzyme glutamine synthetase (GS). The 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 with controls, the circulating concentration and net production of glutamine across the hindquarter were not different in fed GS-KO/M mice. Only a approximately 3-fold higher escape of ammonia revealed the absence of GS in muscle. However, after 20 h of fasting, GS-KO/M mice were not able to mount the approximately 4-fold increase in glutamine production across the hindquarter that was observed in control mice. Instead, muscle ammonia production was approximately 5-fold higher than in control mice. The fasting-induced metabolic changes were transient and had returned to fed levels at 36 h 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 approximately 2.5 micromol ammonia/g muscle.h 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.
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Youji
authors.initials: Y
authors.lastname: He
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Theodorus B M
authors.initials: TBM
authors.lastname: Hakvoort
authors.affiliation: Departments of Anatomy & Embryology and Surgery, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: S Eleonore
authors.initials: SE
authors.lastname: Köhler
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Jacqueline L M
authors.initials: JLM
authors.lastname: Vermeulen
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: D Rudi
authors.initials: DR
authors.lastname: de Waart
authors.affiliation: Departments of Anatomy & Embryology and Surgery, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Chiel
authors.initials: C
authors.lastname: de Theije
authors.affiliation: University of Maastricht, 6200 MD Maastricht, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Gabrie A M
authors.initials: GAM
authors.lastname: Ten Have
authors.affiliation: University of Maastricht, 6200 MD Maastricht, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Hans M H
authors.initials: HMH
authors.lastname: van Eijk
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Cindy
authors.initials: C
authors.lastname: Kunne
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Wilhelmina T
authors.initials: WT
authors.lastname: Labruyere
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolovic
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ruijter
authors.affiliation: University of Maastricht, 6200 MD Maastricht, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Nicolaas E P
authors.initials: NEP
authors.lastname: Deutz
authors.affiliation: Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam; Departments of Anatomy & Embryology and Surgery, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Electronic address: w.h.lamers@amc.uva.nl.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
mesh_terms: D000483:Alleles; D000641:Ammonia / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D005260:Female; D005508:Food Deprivation; D005838:Genotype; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology; D009132:Muscles / Q000201:enzymology*; D012737:Sex Factors; D014508:Urea / Q000737:chemistry
chemical_list: D005973:Glutamine; D000641:Ammonia; D014508:Urea; D005974:Glutamate-Ammonia Ligase