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-kappaB and its target genes. Here, we show that a downstream target of NF-kappaB 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-kappaB, it did not trigger MyoD mRNA degeneration, demonstrating that NF-kappaB-mediated muscle wasting requires an active iNOS-NO pathway. The induced expression of iNOS by cytokines relies on both transcriptional activation via NF-kappaB 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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Di Marco S,Mazroui R,Dallaire P,Chittur S,Tenenbaum SA,Radzioch D,Marette A,Gallouzi IEdoi
10.1128/MCB.25.15.6533-6545.2005subject
Has Abstractpub_date
2005-08-01 00:00:00pages
6533-45issue
15eissn
0270-7306issn
1098-5549pii
25/15/6533journal_volume
25pub_type
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