Ames Dwarf (Prop1df/Prop1df) mice display increased sensitivity of the major GH-signaling pathways in liver and skeletal muscle

JOHANNA G. MIQUET; ANA I. SOTELO; MARINA C. MUÑOZ; JORGE F. GIANI; LORENA GONZÁLEZ; FERNANDO P. DOMINICI; ANDRZEJ BARTKE; DANIEL TURYN

Turín, Italia

Simposio; 1st Basic Postgraduate Course of the European Society for Endocrinology: Endocrinology meets Science; 2009

Contribution Growth hormone (GH) is an anabolic hormone that regulates growth and metabolism. Ames dwarf mice are natural mutants for Prop-1, with impaired development of anterior pituitary and undetectable levels of circulating GH, prolactin and TSH. They constitute an endocrine model of life-long GH deficiency [1]. The principal signaling cascades activated by GH binding to its receptor are the JAK2/STATs, PI-3K/Akt and the MAPK Erk 1/2 pathways [2]. We have previously reported that GH-induced STAT5 activation was higher in Ames dwarf mice liver, compared to nondwarf controls [3]. The aim of the present study was to evaluate the principal components of the main GH-signaling pathways in liver and skeletal muscle, another GH-target tissue, under GH-deficiency. Ames dwarf mice and their non-dwarf siblings were injected i.p. with GH or saline 15 minutes before tissue removal. Protein content and phosphorylation of signaling mediators were determined by immunoblotting of tissue solubilizates. GH was able to induce STAT5 and STAT3 phosphorylation in both tissues, but the response was higher for Ames dwarf mice than for non-dwarf controls. GH-induced Akt phosphorylation at Ser473 in liver was only detected in dwarf mice, while both normal and dwarf mice responded to a GH stimulus in skeletal muscle, although dwarf mice presented higher GH activation levels. When Erk1/2 activation was assessed in liver, only dwarf mice showed GH-induced phosphorylation, while in muscle no response to the hormone was found in either genotype. Protein content of the signaling mediators studied did not vary between normal and dwarf animals in the evaluated tissues. The results show that for the main GH signaling pathways, Ames dwarf mice exhibit enhanced sensitivity to the hormone in liver and muscle.   REFERENCE LIST [1] Bartke A, Brown-Borg. Life extension in the dwarf mice. Curr Top Dev Biol. 2004 63:189-225 [2] Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2007 7:225-235 [3] Miquet JG, Sotelo AI, Dominici FP, Bonkowski MS, Bartke A, Turyn D. Increased sensitivity to GH in liver of Ames dwarf (Prop1df/ Prop1df) mice related to diminished CIS abundance. J Endocrinol. 2005 187:387-397