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Molecular and Cellular Biology, August 2005, p. 6533-6545, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6533-6545.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B-Mediated MyoD Decay during Muscle Wasting Requires Nitric Oxide Synthase mRNA Stabilization, HuR Protein, and Nitric Oxide Release{dagger}

Sergio Di Marco,1 Rachid Mazroui,1 Patrice Dallaire,4 Sridar Chittur,2 Scott A. Tenenbaum,2 Danuta Radzioch,3 Andre Marette,4 and Imed-Eddine Gallouzi1*

Department of Biochemistry, McGill University, Montreal, Quebec, Canada,1 Department of Biomedical Sciences, GenNYSis Center of Excellence in Cancer Genomics and the Center for Functional Genomics, University at Albany-SUNY, Albany, New York,2 Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada,3 Department of Anatomy and Physiology and Lipid Research Unit, Laval University Hospital Research, Sainte-Foy, Quebec, Canada4

Received 24 March 2005/ Returned for modification 26 April 2005/ Accepted 12 May 2005

Muscle wasting (cachexia) is a consequence of chronic diseases, such as cancer, and is associated with degradation of muscle proteins such as MyoD. The cytokines tumor necrosis factor alpha and gamma interferon induce muscle degeneration by activating the transcription factor NF-{kappa}B and its target genes. Here, we show that a downstream target of NF-{kappa}B is the nitric oxide (NO) synthase gene (iNos) and suggest that NO production stimulates MyoD mRNA loss. In fact, although cytokine treatment of iNos–/– mice activated NF-{kappa}B, it did not trigger MyoD mRNA degeneration, demonstrating that NF-{kappa}B-mediated muscle wasting requires an active iNOS-NO pathway. The induced expression of iNOS by cytokines relies on both transcriptional activation via NF-{kappa}B and increased mRNA stability via the RNA-binding protein HuR. Moreover, we show that HuR regulates iNOS expression in an AMP-activated protein kinase (AMPK)-dependent manner. Furthermore, AMPK activation results in HuR nuclear sequestration, inhibition of iNOS synthesis, and reduction in cytokine-induced MyoD loss. These results define iNOS and HuR as critical players in cytokine-induced cachexia, establishing them as potential therapeutic targets.

* Corresponding author. Mailing address: Department of Biochemistry, McGill University, McIntyre Building, room 904, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Phone: (514) 398-4537. Fax: (514) 398-7384. E-mail: imed.gallouzi{at}mcgill.ca.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 6533-6545, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6533-6545.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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