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The Orphan Nuclear Receptor, NOR-1, Is a Target of ß-Adrenergic Signaling in Skeletal Muscle

Institute for Molecular Bioscience (M.A.P., M.A.M., G.E.O.M.), Division of Molecular Genetics and Development, University of Queensland, St. Lucia, Queensland 4072, Australia; Basic and Clinical Myology Laboratory (J.G.R., G.S.L.), Department of Physiology, The University of Melbourne, Victoria 3010, Australia; and Tumor Endocrinology Project (N.O.), National Cancer Center Research Institute, Tokyo 104-0045, Japan

Address all correspondence and requests for reprints to: George E. O. Muscat, Institute for Molecular Bioscience, Division of Molecular Genetics and Development, University of Queensland, St. Lucia, Queensland 4072, Australia. E-mail: g.muscat{at}imb.uq.edu.au.

ß-Adrenergic receptor (ß-AR) agonists induce Nur77 mRNA expression in the C2C12 skeletal muscle cell culture model and elicit skeletal muscle hypertrophy. We previously demonstrated that Nur77 (NR4A1) is involved in lipolysis and gene expression associated with the regulation of lipid homeostasis. Subsequently it was demonstrated by another group that ß-AR agonists and cold exposure-induced Nur77 expression in brown adipocytes and brown adipose tissue, respectively. Moreover, NOR-1 (NR4A3) was hyperinduced by cold exposure in the nur77^–/– animal model. These studies underscored the importance of understanding the role of NOR-1 in skeletal muscle. In this context we observed 30–480 min of ß-AR agonist treatment significantly and transiently increased expression of the orphan nuclear receptor NOR-1 in both mouse skeletal muscle tissue (plantaris) and C2C12 skeletal muscle cells. Specific ß₂- and ß₃-AR agonists had similar effects as the pan-agonist and were blocked by the ß-AR antagonist propranolol. Moreover, in agreement with these observations, isoprenaline also significantly increased the activity of the NOR-1 promoter. Stable exogenous expression of a NOR-1 small interfering RNA (but not the negative control small interfering RNA) in skeletal muscle cells significantly repressed endogenous NOR-1 mRNA expression and led to changes in the expression of genes involved in the control of lipid use and muscle mass underscored by a dramatic increase in myostatin mRNA expression. Concordantly the myostatin promoter was repressed by NOR-1 expression. In conclusion, NOR-1 is highly responsive to ß-adrenergic signaling and regulates the expression of genes controlling fatty acid use and muscle mass.

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