The orphan nuclear receptor, NOR-1, is a target of beta-adrenergic signaling in skeletal muscle.
beta-Adrenergic receptor (beta-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 beta-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 beta-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 beta(2)- and beta(3)-AR agonists had similar effects as the pan-agonist and were blocked by the beta-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 beta-adrenergic signaling and regulates the expression of genes controlling fatty acid use and muscle mass.
Pearen
Michael A
MA
Institute for Molecular Bioscience, Division of Molecular Genetics and Development, University of Queensland, St. Lucia, Queensland 4072, Australia.
Ryall
James G
JG
Maxwell
Megan A
MA
Ohkura
Naganari
N
Lynch
Gordon S
GS
Muscat
George E O
GE
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D007473:Ion Channels / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D050356:Lipid Metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000502:physiology; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D055435:Myostatin; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D004268:DNA-Binding Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; C525912:Mstn protein, mouse; D055435:Myostatin; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011943:Receptors, Adrenergic, beta; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D007545:Isoproterenol