Effect of Growth Hormone in an Experimental Model of Protein Hypercatabolism Induced by Glucocorticoids

Abstract

Objective: The aims of the study were to evaluate whether growth hormone could be beneficial in a model of hypercatabolism induced by glucocorticoids and to examine its effects on ACTH, corticosterone and IGF-1 levels. The effects of growth hormone on the expression of both glucocorticoid receptor and tyrosine aminotransferase were also evaluated. Methods: Fifty Wistar rats were divided into five groups and treated as follows: (A) daily subcutaneous injection of growth hormone (4.8 IU/kg/day) and oral placebo, (B) daily injection of placebo and oral dexamethasone (3 mg/kg/day), (C) daily injection of growth hormone and oral dexamethasone, (D) daily injection of placebo and oral placebo, and (E) no treatment. The animals were decapitated seven days after initiating treatment. Results: Growth hormone did not modify the weight loss induced by dexamethasone. Glucocorticoid receptor expression was significantly lower in group A than in group E. An increase in tyrosine aminotransferase was observed in group C. Conclusion: Growth hormone did not exert any beneficial effect in this model of hypercatabolism. Growth hormone decreased glucocorticoid receptor expression. This fact could explain its beneficial effect when protein hypercatabolism is not the predominant phenomenon. Growth hormone induced the hyperexpression of tyrosine aminotransferase, thus suggesting an amplifying effect on the glucocorticoid action.

Hypermetabolism - catabolism - dexamethasone - tyrosine transaminase - ACTH - corticosterone - IGF-1 levels

References

• 1 Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Intz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorne M. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee.  J Clin Endocrinol Metab. 1998;  83 382-395
• 2 Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency.  N Engl J Med. 1989;  321 1797-1803
• 3 Russell-Jones DL, Weissberger AJ, Bowes SB, Kelly JM, Thomason M, Umpleby AM, Jones RH, Sonksen PH. The effects of growth hormone on protein metabolism in adult growth hormone deficient patients.  Clin Endocrinol (Oxf). 1993;  38 427-431
• 4 Hasselgren PO. Glucocorticoids and muscle catabolism.  Curr Opin Clin Nutr Metab Care. 1999;  2 201-205
• 5 Tomas FM, Knowles SE, Owens PC, Chandler CS, Francis GL, Read LC, Ballard FJ. Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats.  Biochem J. 1992;  282 91-97
• 6 Ortoft G, Kelly C, Brüel A, Smith A, Carter N, Oxlund H. Glucocorticoids inhibit the growth hormone induced increase in serum IGF-1 and its mRNA, body weight and muscle mass of rats.  Eur J Exp Musculoskel Res. 1993;  2 135-142
• 7 Auclair D, Garrel DR, Chaouki ZA, Ferland LH. Activation of the ubiquitin pathway in rat skeletal muscle by catabolic doses of glucocorticoids.  Am J Physiol. 1997;  272 C1007-C1016
• 8 Boctor A, Grossman A. Alteration of tyrosine aminotransferase turnover in rat liver following glucocorticoid administration.  J Biol Chem. 1970;  245 6337-6345
• 9 Chrysis D, Underwood LE. Regulation of components of the ubiquitin system by insulin-like growth factor 1 and growth hormone in skeletal muscle of rats made catabolic with dexamethasone.  Endocrinology. 1999;  140 5635-5641
• 10 Malmlof K, Arrhenius-Nyberg V, Saxerholt H, Skottner A. The role of insulin, insulin-like growth factor-I and growth hormone in counteracting dexamethasone induced nitrogen wasting in rats.  Horm Metab Res. 1997;  29 20-24
• 11 Savary I, Debras E, Dardevet D, Sornet C, Capitan P, Prugnaud, J Mirand PP, Grizard J. Effect of glucocorticoid excess on skeletal muscle and heart protein synthesis in adult and old rats.  Br J Nutr. 1998;  79 297-304
• 12 Dardevet D, Sornet C, Savary I, Debras E, Patureau-Mirand P, Grizard J. Glucocorticoid effects on insulin- and IGF-I-regulated muscle protein metabolism during aging.  J Endocrinol. 1998;  156 83-89
• 13 Fazio S, Palmieri EA, Biondi B, Cittadini A, Sacca L. The role of the GH-IGF-I axis in the regulation of myocardial growth: from experimental models to human evidence.  Eur J Endocrinol. 2000;  142 211-216
• 14 Genth-Zotz S, Zotz R, Geil S, Voigtlander T, Meyer J, Darius H. Recombinant growth hormone therapy in patients with ischemic cardiomyopathy: effects on hemodynamics, left ventricular function, and cardiopulmonary exercise capacity.  Circulation. 1999;  99 18-21
• 15 Fazio S, Sabatini D, Capaldo B, Vigorito C, Giordano A, Guida R, Pardo F, Biondi B, Sacca L. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy.  N Engl J Med. 1996;  334 809-814
• 16 Hellstern G, Reijngoud DJ, Stellaard F, Okken A. Insulin-like growth factor-I fails to reverse corticosteroid-induced protein catabolism in growing piglets.  Pediatr Res. 1996;  39 421-426
• 17 Jenkins RC, Ross RJ. Growth hormone therapy for protein catabolism.  QJM. 1996;  89 813-819
• 18 Ross R, Miell J, Freeman E, Jones J, Matthews D, Preece M, Buchanan C. Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I.  Clin Endocrinol (Oxf). 1991;  35 47-54
• 19 Singleton JR, Baker BL, Thorburn A. Dexamethasone inhibits insulin-like growth factor signaling and potentiates myoblast apoptosis.  Endocrinology. 2000;  141 2945-2950
• 20 Skottner A, Clark RG, Fryklund L, Robinson IC. Growth responses in a mutant dwarf rat to human growth hormone and recombinant human insulin-like growth factor-I.  Endocrinology. 1989;  124 2519-2526
• 21 DuBois DC, Xu ZX, McKay L, Almon RR, Pyszcznski N, Jusko WJ. Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment.  J Steroid Biochem Mol Biol. 1995;  54 237-243
• 22 Yoshida A, Noguchi T, Taniguchi S, Mitani Y, Ueda M, Urabe K, Adachi T, Okamura Y, Shigemasa C, Abe K. Receptor dynamics and tyrosine aminotransferase induction during the course of chronic treatment of rats with glucocorticoid.  Endocrinol Jpn. 1986;  33 769-775
• 23 Izawa M, Yoshida A, Ichii S. Dynamics of glucocorticoid receptor and induction of tyrosine aminotransferase in rat liver.  Endocrinol Jpn. 1982;  29 209-218
• 24 Kalinyak JE, Dorin RI, Hoffman AR, Perlman AJ. Tissue-specific regulation of glucocorticoid receptor mRNA by dexamethasone.  J Biol Chem. 1987;  262 10441-10444
• 25 Dong Y, Poellinger L, Gustafsson JA, Okret S. Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms.  Mol Endocrinol. 1988;  2 1256-1264
• 26 Chesnokov VN, Gadzhiev VG, Leontyeva GI, Zelenin SM, Mertvetsov NP. Hydrocortisone regulation and expression of tyrosine aminotransferase gene in various tissues of rat.  Biomed Biochim Acta. 1990;  49 1177-1186
• 27 Haughey DB, Jusko WJ. Receptor-mediated methylprednisolone pharmacodynamics in rats: steroid-induced receptor down-regulation.  J Pharmacokinet Biopharm. 1992;  20 333-355
• 28 Liberti JP, Longman ES, Navon RS. Effects of hydrocortisone and growth hormone on tyrosine aminotransferase and tryptophan oxygenase levels in hypophysectomized rats.  Endocrinology. 1970;  86 1448-1450
• 29 Schapiro S. Interaction between growth hormone and cortisol on the regulation of liver tyrosine transaminase activity.  Endocrinology. 1968;  83 475-478
• 30 Shirwany TA, Hubbard JR, Kalimi M. Glucocorticoid regulation of hepatic cytosolic glucocorticoid receptors in vivo and its relationship to induction of tyrosine aminotransferase.  Biochim Biophys Acta. 1986;  886 162-168
• 31 Sakuma T, Kitajima K, Nishiyama M, Endo Y, Miyauchi K, Jarukamjorn K, Nemoto N. Collaborated regulation of female-specific murine Cyp3a41 gene expression by growth and glucocorticoid hormones.  Biochem Biophys Res Commun. 2004;  314 495-500
• 32 Rastegar M, Rousseau GG, Lemaigre FP. CCAAT/enhancer-binding protein-alpha is a component of the growth hormone-regulated network of liver transcription factors.  Endocrinology. 2000;  141 1686-1692
• 33 Samadani U, Porcella A, Pani L, Johnson PF, Burch JB, Pine R, Costa RH. Cytokine regulation of the liver transcription factor hepatocyte nuclear factor-3 beta is mediated by the C/EBP family and interferon regulatory factor 1.  Cell Growth Differ. 1995;  6 879-890
• 34 Landry C, Clotman F, Hioki T, Oda H, Picard JJ, Lemaigre FP, Rousseau GG. HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors.  Dev Biol. 1997;  192 247-257
• 35 Lahuna O, Rastegar M, Maiter D, Thissen JP, Lemaigre FP, Rousseau GG. Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone.  Mol Endocrinol. 2000;  14 285-294
• 36 Lahuna O, Fernández L, Karlsson H, Maiter D, Lemaigre FP, Rousseau GG, Gustafsson J, Mode A. Expression of hepatocyte nuclear factor 6 in rat liver is sex-dependent and regulated by growth hormone.  Proc Natl Acad Sci USA. 1997;  94 12309-12313
• 37 Kaestner KH, Hiemisch H, Schutz G. Targeted disruption of the gene encoding hepatocyte nuclear factor 3γ results in reduced transcription of hepatocyte-specific genes.  Mol Cell Biol. 1998;  18 4245-4251
• 38 Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults.  N Engl J Med. 1999;  341 785-792

Correspondence