Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification

被引:67
作者
He, Youji [1 ,2 ]
Hakvoort, Theodorus B. M. [1 ,2 ]
Kohler, S. Eleonore [3 ]
Vermeulen, Jacqueline L. M. [1 ,2 ]
de Waart, D. Rudi [1 ,2 ]
de Theije, Chiel [3 ]
ten Have, Gabrie A. M. [4 ]
van Eijk, Hans M. H. [4 ]
Kunne, Cindy [1 ,2 ]
Labruyere, Wilhelmina T. [1 ,2 ]
Houten, Sander M. [5 ]
Sokolovic, Milka [1 ,2 ]
Ruijter, Jan M. [1 ,2 ]
Deutz, Nicolaas E. P. [4 ]
Lamers, Wouter H. [1 ,2 ,3 ]
机构
[1] Univ Amsterdam, Acad Med Ctr, Ctr Liver, NL-1105 BK Amsterdam, Netherlands
[2] Univ Amsterdam, Acad Med Ctr, Dept Anat & Embryol, NL-1105 BK Amsterdam, Netherlands
[3] Univ Maastricht, Dept Anat & Embryol, NL-6200 MD Maastricht, Netherlands
[4] Univ Maastricht, Dept Surg, NL-6200 MD Maastricht, Netherlands
[5] Univ Amsterdam, Acad Med Ctr, Lab Genet Metab Dis, NL-1105 AZ Amsterdam, Netherlands
关键词
METHIONINE-DL-SULFOXIMINE; ACUTE LIVER-FAILURE; SKELETAL-MUSCLE; AMINO-ACIDS; PROTEIN BREAKDOWN; WHOLE-BODY; IN-VIVO; METABOLISM; EXPRESSION; RATS;
D O I
10.1074/jbc.M109.092429
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 similar to 3-fold higher escape of ammonia revealed the absence of GS in muscle. However, after 20 h of fasting, GSKO/M mice were not able to mount the similar to 4-fold increase in glutamine production across the hindquarter that was observed in control mice. Instead, muscle ammonia production was similar to 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 similar to 2.5 mu mol ammonia/g muscle.h in a muscle GS-dependent manner, with simultaneous accumulation of urea, whereas GSKO/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.
引用
收藏
页码:9516 / 9524
页数:9
相关论文
共 50 条
[1]   LONG-TERM EFFECTS OF THE ADMINISTRATION OF THE CONVULSIVE SUBSTANCE DL-METHIONINE-DL-SULFOXIMINE TO THE RABBIT [J].
APOSTOLAKIS, M ;
ANOGIANAKIS, G ;
KALLARAS, C ;
ZARABOUKAS, T ;
LIANGOURIS, J ;
NOWACKAPOSTOLAKI, E ;
ECONOMOU, L .
BRAIN RESEARCH BULLETIN, 1989, 23 (03) :257-262
[2]   CHANGES IN GLUTAMINE-SYNTHETASE ACTIVITY IN THE DIFFERENT ORGANS OF DEVELOPING RATS [J].
AROLA, L ;
PALOU, A ;
REMESAR, X ;
ALEMANY, M .
ARCHIVES INTERNATIONALES DE PHYSIOLOGIE DE BIOCHIMIE ET DE BIOPHYSIQUE, 1981, 89 (03) :189-194
[3]   GLUTAMINE-SYNTHETASE MESSENGER-RNA IN CULTURED 3T3-L1 ADIPOCYTES - COMPLEXITY, CONTENT AND HORMONAL-REGULATION [J].
BHANDARI, B ;
BURNS, DM ;
HOFFMAN, RC ;
MILLER, RE .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1986, 47 (1-2) :49-57
[4]   Inhibition of muscle glutamine formation in hypercatabolic patients [J].
Biolo, G ;
Fleming, RYD ;
Maggi, SP ;
Nguyen, TT ;
Herndon, DN ;
Wolfe, RR .
CLINICAL SCIENCE, 2000, 99 (03) :189-194
[5]   Muscle glutamine depletion in the intensive care unit [J].
Biolo, G ;
Zorat, F ;
Antonione, R ;
Ciocchi, B .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2005, 37 (10) :2169-2179
[6]   TRANSMEMBRANE TRANSPORT AND INTRACELLULAR KINETICS OF AMINO-ACIDS IN HUMAN SKELETAL-MUSCLE [J].
BIOLO, G ;
FLEMING, RYD ;
MAGGI, SP ;
WOLFE, RR .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1995, 268 (01) :E75-E84
[7]   A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance [J].
Bruning, JC ;
Michael, MD ;
Winnay, JN ;
Hayashi, T ;
Horsch, D ;
Accili, D ;
Goodyear, LJ ;
Kahn, CR .
MOLECULAR CELL, 1998, 2 (05) :559-569
[8]  
CHANG TW, 1978, J BIOL CHEM, V253, P3677
[9]  
CHANG TW, 1978, J BIOL CHEM, V253, P3685
[10]   Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure [J].
Chatauret, Nicolas ;
Desjardins, Paul ;
Zwingmann, Claudia ;
Rose, Christopher ;
Rao, K. V. Rama ;
Butterworth, Roger F. .
JOURNAL OF HEPATOLOGY, 2006, 44 (06) :1083-1088