NF-κB-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release

Sergio Di Marco, Rachid Mazroui, Patrice Dallaire, Sridar Chittur, Scott A. Tenenbaum, Danuta Radzioch, Andre Marette, Imed Gallouzi

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

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-κB and its target genes. Here, we show that a downstream target of NF-κB 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-κB, it did not trigger MyoD mRNA degeneration, demonstrating that NF-κB-mediated muscle wasting requires an active iNOS-NO pathway. The induced expression of iNOS by cytokines relies on both transcriptional activation via NF-κB 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.

Original languageEnglish
Pages (from-to)6533-6545
Number of pages13
JournalMolecular and Cellular Biology
Volume25
Issue number15
DOIs
Publication statusPublished - Aug 2005
Externally publishedYes

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Nitric Oxide Synthase
Nitric Oxide
Cytokines
Muscles
Messenger RNA
Cachexia
AMP-Activated Protein Kinases
Activating Transcription Factors
RNA-Binding Proteins
Muscle Proteins
RNA Stability
Interferon-alpha
Transcriptional Activation
Genes
Interferon-gamma
Chronic Disease
Tumor Necrosis Factor-alpha
ELAV-Like Protein 1
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

NF-κB-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release. / Di Marco, Sergio; Mazroui, Rachid; Dallaire, Patrice; Chittur, Sridar; Tenenbaum, Scott A.; Radzioch, Danuta; Marette, Andre; Gallouzi, Imed.

In: Molecular and Cellular Biology, Vol. 25, No. 15, 08.2005, p. 6533-6545.

Research output: Contribution to journalArticle

Di Marco, Sergio ; Mazroui, Rachid ; Dallaire, Patrice ; Chittur, Sridar ; Tenenbaum, Scott A. ; Radzioch, Danuta ; Marette, Andre ; Gallouzi, Imed. / NF-κB-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 15. pp. 6533-6545.
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