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Submitted on April 3, 2007
Accepted on May 30, 2007
Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA, Dept. of Biochemistry, Boston University Medical Center, 715 Albany St., Boston, MA, USA, The Center for Diabetes, Endocrinology and Metabolism, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, California, USA
* To whom correspondence should be addressed. E-mail: ptontonoz{at}mednet.ucla.edu.
Innervation is important for normal metabolism in skeletal muscle, including insulin-sensitive glucose uptake. However, the transcription factors that transduce signals from the neuromuscular junction to the nucleus and affect changes in metabolic gene expression are not well defined. We demonstrate here that the orphan nuclear receptor Nur77 is a regulator of gene expression linked to glucose utilization in muscle. In vivo, Nur77 is preferentially expressed in glycolytic compared to oxidative muscle and is responsive to 
-adrenergic stimulation. Denervation of rat muscle compromises expression of Nur77 in parallel with that of numerous genes linked to glucose metabolism, including GLUT4 and genes involved in glycolysis, glycogenolysis, and the glycerophosphate shuttle. Ectopic expression of Nur77, either in rat muscle or in C2C12 muscle cells, induces expression of a highly overlapping set of genes, including GLUT4, muscle phosphofructokinase, and glycogen phosphorylase. Furthermore, selective knockdown of Nur77 in rat muscle by shRNA or genetic deletion of Nur77 in mice reduces the expression of a battery of genes involved in skeletal muscle glucose utilization in vivo. Finally, we show that Nur77 binds the promoter regions of multiple genes involved in glucose metabolism in muscle. These results identify Nur77 as a potential mediator of neuromuscular signaling in the control of metabolic gene expression.
NURSA Molecule Pages Link:
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