Glutamine synthetase in muscle is required for glutamine production during fasting and extrahepatic ammonia detoxification.
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.
He
Youji
Y
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
Hakvoort
Theodorus B M
TBM
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
Köhler
S Eleonore
SE
Departments of Anatomy & Embryology and Surgery, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Vermeulen
Jacqueline L M
JLM
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
de Waart
D Rudi
DR
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
de Theije
Chiel
C
Departments of Anatomy & Embryology and Surgery, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Ten Have
Gabrie A M
GAM
University of Maastricht, 6200 MD Maastricht, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
van Eijk
Hans M H
HMH
University of Maastricht, 6200 MD Maastricht, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Kunne
Cindy
C
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
Labruyere
Wilhelmina T
WT
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
Houten
Sander M
SM
Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Sokolovic
Milka
M
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
Ruijter
Jan M
JM
Academic Medical Center Liver Center and Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam.
Deutz
Nicolaas E P
NEP
University of Maastricht, 6200 MD Maastricht, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Lamers
Wouter H
WH
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.
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
D005973:Glutamine; D000641:Ammonia; D014508:Urea; D005974:Glutamate-Ammonia Ligase