Arginine deficiency causes runting in the suckling period by selectively activating the stress kinase GCN2.
Suckling "F/A2" mice, which overexpress arginase-I in their enterocytes, develop a syndrome (hypoargininemia, reduced hair and muscle growth, impaired B-cell maturation) that resembles IGF1 deficiency. The syndrome may result from an impaired function of the GH-IGF1 axis, activation of the stress-kinase GCN2, and/or blocking of the mTORC1-signaling pathway. Arginine deficiency inhibited GH secretion and decreased liver Igf1 mRNA and plasma IGF1 concentration, but did not change muscle IGF1 concentration. GH supplementation induced Igf1 mRNA synthesis, but did not restore growth, ruling out direct involvement of the GH-IGF1 axis. In C2C12 muscle cells, arginine withdrawal activated GCN2 signaling, without impacting mTORC1 signaling. In F/A2 mice, the reduction of plasma and tissue arginine concentrations to ∼25% of wild-type values activated GCN2 signaling, but mTORC1-mediated signaling remained unaffected. Gcn2-deficient F/A2 mice suffered from hypoglycemia and died shortly after birth. Because common targets of all stress kinases (eIF2α phosphorylation, Chop mRNA expression) were not increased in these mice, the effects of arginine deficiency were solely mediated by GCN2.
Dept of Anatomy & Embryology and NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Vincent
V
Marion
Selvakumari
S
Sankaranarayanan
Chiel
C
de Theije
Paul
P
van Dijk
Patrick
P
Lindsey
Marinus C
MC
Lamers
Heather P
HP
Harding
David
D
Ron
Wouter H
WH
Lamers
S Eleonore
SE
Köhler
D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D001120:Arginine / Q000172:deficiency* / Q000235:genetics; D001402:B-Lymphocytes / Q000201:enzymology; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D006201:Hair Diseases / Q000201:enzymology / Q000235:genetics; D007003:Hypoglycemia / Q000201:enzymology / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins; D015398:Signal Transduction; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases
D046912:Multiprotein Complexes; D011506:Proteins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D001120:Arginine; C070634:Eif2ak4 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C544448:Arg1 protein, mouse; D001119:Arginase
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