This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Frost, R. A. Articles by Lang, C. H. Search for Related Content PubMed PubMed Citation Articles by Frost, R. A. Articles by Lang, C. H.

Regulation of IGF-I mRNA and Signal Transducers and Activators of Transcription-3 and -5 (Stat-3 and -5) by GH in C2C12 Myoblasts

Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Robert A. Frost, Ph.D., Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey Medical Center, H166, Hershey, Pennsylvania 17033. E-mail: rfrost{at}psu.edu

GH and IGF-I are critical hormones for the regulation of longitudinal growth and the maintenance of lean body mass in humans. The regulation of IGF-I expression by GH in hepatocytes is well documented; however less is known about the regulation of IGF-I in peripheral tissues such as muscle. We have examined the regulation of IGF-I mRNA by GH and IGF-I in C2C12 myoblasts. GH stimulated the accumulation of IGF-I mRNA dose- and time-dependently. An elevation of IGF-I mRNA was observed with GH doses as low as 0.75 ng/ml and after exposure to GH for as little as 1 h, and the increase required ongoing transcription and translation. GH applied in a pulsatile fashion for 10 min followed by an 8-h interpulse interval increased IGF-I mRNA to a greater extent than continuous exposure. GH stimulated tyrosine phosphorylation of the GH receptor, signal transducer and activator of transcription-3 (Stat3), and Stat5. Stat5 was resistant to additional phosphorylation if cells were given a GH pulse within 2 h of a previous GH exposure. The refractory period lasted for 4 h, and cells could be maximally stimulated again after 6 h. Stat3 phosphorylation was also enhanced in cells that were allowed to recover from a previous application of GH. The tyrosine kinase inhibitors, genistein, PP1, and AG-490, and the MAPK kinase inhibitor, PD98059, did not block Stat3 or Stat5 phosphorylation. In contrast, WHI-P154, a Janus kinase-3 inhibitor, dose-dependently prevented Stat3, but not Stat5, phosphorylation. GH-inducible nuclear transport of Stat3 was likewise inhibited by WHI-P154. Most importantly, GH-dependent IGF-I mRNA expression was inhibited by WHI-P154. In contrast, IGF-I mRNA expression was inhibited by IGF-I peptide, and the effect of IGF-I was dominant over that of GH. IGF-I mRNA was regulated by both PI3K and MAPK signal transduction pathways, but IGF-I peptide signaled predominantly through a wortmannin-sensitive pathway to down-regulate its own mRNA. Our data suggest that Janus kinases (Jak2 or Jak3) and their downstream targets (Stat3 and Stat5) may play important roles in the expression of IGF-I mRNA and the myoblast response to GH. In addition, C2C12 cells appear to be a good model system to examine GH regulation of Janus kinase/Stat signaling and the regulation of IGF-I mRNA.

This article has been cited by other articles:

				C. Nielsen, L. C. Gormsen, N. Jessen, S. B. Pedersen, N. Moller, S. Lund, and J. O. L. Jorgensen Growth Hormone Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background, and Growth Hormone Receptor Blockade J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2842 - 2850. [Abstract] [Full Text] [PDF]

				F. A. Wilson, R. A. Orellana, A. Suryawan, H. V. Nguyen, A. S. Jeyapalan, J. Frank, and T. A. Davis Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E187 - E194. [Abstract] [Full Text] [PDF]

				T. H. Elsasser, C.-J. Li, T. J. Caperna, S. Kahl, and W. F. Schmidt Growth Hormone (GH)-Associated Nitration of Janus Kinase-2 at the 1007Y-1008Y Epitope Impedes Phosphorylation at This Site: Mechanism for and Impact of a GH, AKT, and Nitric Oxide Synthase Axis on GH Signal Transduction Endocrinology, August 1, 2007; 148(8): 3792 - 3802. [Abstract] [Full Text] [PDF]

				S. J. Frank Growth Hormone, Insulin-Like Growth Factor I, and Growth: Local Knowledge Endocrinology, April 1, 2007; 148(4): 1486 - 1488. [Full Text] [PDF]

				M. K. Trenerry, K. A. Carey, A. C. Ward, and D. Cameron-Smith STAT3 signaling is activated in human skeletal muscle following acute resistance exercise J Appl Physiol, April 1, 2007; 102(4): 1483 - 1489. [Abstract] [Full Text] [PDF]

				P. Klover and L. Hennighausen Postnatal Body Growth Is Dependent on the Transcription Factors Signal Transducers and Activators of Transcription 5a/b in Muscle: A Role for Autocrine/Paracrine Insulin-Like Growth Factor I Endocrinology, April 1, 2007; 148(4): 1489 - 1497. [Abstract] [Full Text] [PDF]

				A. P. Tuckow, K. R. Rarick, W. J. Kraemer, J. O. Marx, W. C. Hymer, and B. C. Nindl Nocturnal growth hormone secretory dynamics are altered after resistance exercise: deconvolution analysis of 12-hour immunofunctional and immunoreactive isoforms Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1749 - R1755. [Abstract] [Full Text] [PDF]

				M. Adriani, C. Garbi, G. Amodio, I. Russo, M. Giovannini, S. Amorosi, E. Matrecano, E. Cosentini, F. Candotti, and C. Pignata Functional Interaction of Common {gamma}-Chain and Growth Hormone Receptor Signaling Apparatus J. Immunol., November 15, 2006; 177(10): 6889 - 6895. [Abstract] [Full Text] [PDF]

				A M Solomon and P M G Bouloux Modifying muscle mass - the endocrine perspective. J. Endocrinol., November 1, 2006; 191(2): 349 - 360. [Abstract] [Full Text] [PDF]

				J. O. L. Jorgensen, N. Jessen, S. B. Pedersen, E. Vestergaard, L. Gormsen, S. A. Lund, and N. Billestrup GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E899 - E905. [Abstract] [Full Text] [PDF]

				A. S. McLellan, T. Kealey, and K. Langlands An E box in the exon 1 promoter regulates insulin-like growth factor-I expression in differentiating muscle cells Am J Physiol Cell Physiol, August 1, 2006; 291(2): C300 - C307. [Abstract] [Full Text] [PDF]

				A. Sotiropoulos, M. Ohanna, C. Kedzia, R. K. Menon, J. J. Kopchick, P. A. Kelly, and M. Pende Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation PNAS, May 9, 2006; 103(19): 7315 - 7320. [Abstract] [Full Text] [PDF]

				M. J. Toth, P. A. Ades, M. M. LeWinter, R. P. Tracy, and A. Tchernof Skeletal muscle myofibrillar mRNA expression in heart failure: relationship to local and circulating hormones J Appl Physiol, January 1, 2006; 100(1): 35 - 41. [Abstract] [Full Text] [PDF]

				M. A. Held, W. Cosme-Blanco, L. M. Difedele, E. L. Bonkowski, R. K. Menon, and L. A. Denson Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G986 - G993. [Abstract] [Full Text] [PDF]

				H. Kim, E. Barton, N. Muja, S. Yakar, P. Pennisi, and D. LeRoith Intact Insulin and Insulin-Like Growth Factor-I Receptor Signaling Is Required for Growth Hormone Effects on Skeletal Muscle Growth and Function in Vivo Endocrinology, April 1, 2005; 146(4): 1772 - 1779. [Abstract] [Full Text] [PDF]

				K. Iida, E. Itoh, D.-S. Kim, J. P del Rincon, K. T Coschigano, J. J Kopchick, and M. O Thorner Muscle mechano growth factor is preferentially induced by growth hormone in growth hormone-deficient lit/lit mice J. Physiol., October 15, 2004; 560(2): 341 - 349. [Abstract] [Full Text] [PDF]

				K.-O. Lai, Y. Chen, H.-M. Po, K.-C. Lok, K. Gong, and N. Y. Ip Identification of the Jak/Stat Proteins as Novel Downstream Targets of EphA4 Signaling in Muscle: IMPLICATIONS IN THE REGULATION OF ACETYLCHOLINESTERASE EXPRESSION J. Biol. Chem., April 2, 2004; 279(14): 13383 - 13392. [Abstract] [Full Text] [PDF]

				V. Hwa, B. Little, E. M. Kofoed, and R. G. Rosenfeld Transcriptional Regulation of Insulin-like Growth Factor-I by Interferon-{gamma} Requires STAT-5b J. Biol. Chem., January 23, 2004; 279(4): 2728 - 2736. [Abstract] [Full Text] [PDF]

				R. A. Frost, G. J. Nystrom, and C. H. Lang Lipopolysaccharide and proinflammatory cytokines stimulate interleukin-6 expression in C2C12 myoblasts: role of the Jun NH2-terminal kinase Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1153 - R1164. [Abstract] [Full Text] [PDF]

				C. R. Bruce, A. L. Carey, J. A. Hawley, and M. A. Febbraio Intramuscular Heat Shock Protein 72 and Heme Oxygenase-1 mRNA Are Reduced in Patients With Type 2 Diabetes: Evidence That Insulin Resistance Is Associated With a Disturbed Antioxidant Defense Mechanism Diabetes, September 1, 2003; 52(9): 2338 - 2345. [Abstract] [Full Text] [PDF]

				C. H. Lang, T. C. Vary, and R. A. Frost Acute in Vivo Elevation of Insulin-Like Growth Factor (IGF) Binding Protein-1 Decreases Plasma Free IGF-I and Muscle Protein Synthesis Endocrinology, September 1, 2003; 144(9): 3922 - 3933. [Abstract] [Full Text] [PDF]

				T. E. Childs, E. E. Spangenburg, D. R. Vyas, and F. W. Booth Temporal alterations in protein signaling cascades during recovery from muscle atrophy Am J Physiol Cell Physiol, August 1, 2003; 285(2): C391 - C398. [Abstract] [Full Text] [PDF]

				L. Q. Hong-Brown, C. R. Brown, R. N. Cooney, R. A. Frost, and C. H. Lang Sepsis-induced muscle growth hormone resistance occurs independently of STAT5 phosphorylation Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E63 - E72. [Abstract] [Full Text] [PDF]

				R. A. Frost, G. J. Nystrom, and C. H. Lang Tumor Necrosis Factor-{alpha} Decreases Insulin-Like Growth Factor-I Messenger Ribonucleic Acid Expression in C2C12 Myoblasts via a Jun N-Terminal Kinase Pathway Endocrinology, May 1, 2003; 144(5): 1770 - 1779. [Abstract] [Full Text] [PDF]

				M. M. Buijs, J. A. Romijn, J. Burggraaf, M. L. de Kam, A. F. Cohen, M. Frolich, F. Stellaard, A. E. Meinders, and H. Pijl Growth Hormone Blunts Protein Oxidation and Promotes Protein Turnover to a Similar Extent in Abdominally Obese and Normal-Weight Women J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5668 - 5674. [Abstract] [Full Text] [PDF]