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Original Article

ß-Adrenergic Agonist Hyperplastic Effect Is Associated with Increased Fibronectin Gene Expression and Not Mitogen-Activated Protein Kinase Modulation in C₂C₁₂ Cells

Ernest B. Izevbigie^*,2 and Werner G. Bergen^,1

^* Children's National Medical Center, Washington, D.C. 20010 and The Molecular and Cellular Signaling Unit, National Institutes of Health, Bethesda, Maryland 20892; and
Regulatory Biology Program, Department of Animal and Dairy Sciences, Auburn University, Auburn, Alabama 36849

ß-Adrenergic agonists (ß-AA) enhance protein accretion in skeletal muscles. This stimulation is characterized by increased protein synthesis, increased expression of myofibrillar protein genes and a depression in protein degradation in animals, and increased proliferation and DNA synthesis in muscle cells in vitro. The mechanism or signal path in muscle whereby ß-AA would elicit these physiological effects upon binding to the G protein–coupled ß-adrenergic receptor (ß-AR) is unclear. C₂C₁₂ myoblasts were used to determine ß-AR ligand binding characteristics, cyclic AMP synthesis in response to isoproterenol (ISO) stimulation, and effects of ISO on DNA synthesis, mitogen activated protein kinase (MAPK), and fibronectin (FN) gene expression. Results showed that C₂C₁₂ cells possess ß-AR which are specific, saturable, and of high affinity (K_d = 0.2 nM). Forskolin and ISO stimulated cAMP production by 20-fold (P < 0.001) and 17-fold (P < 0.001), respectively. ISO and the cAMP analog, 8-bromo-cAMP (8-BC) stimulated DNA synthesis in proliferating cells by 150% (P < 0.05) and 200% (P < 0.01), respectively, without modulating MAPK activity, whereas addition of fetal bovine serum to culture resulted in a 500% increase (P < 0.01) in DNA synthesis and MAPK activation. DNA synthesis in C₂C₁₂ cells treated with ISO, 8-BC, or FBS was abolished in the presence of 25 µM PD098059, an MAPK-kinase inhibitor, suggesting that an MAPK-dependent pathway is likely involved in C₂C₁₂ proliferation. During cAMP elevating agent stimulation, basal MAPK activity may be sufficient, in the presence of other putative signaling molecules, to support proliferation in these cells. ISO or 8-BC treatment increased FN mRNA by three- and seven-fold, respectively, in growing C₂C₁₂ cells implying a connection between increased DNA synthesis and FN gene expression.

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