The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice

Sergio Di Marco, Anne Cammas, Xian Jin Lian, Erzsebet Nagy Kovacs, Jennifer F. Ma, Derek T. Hall, Rachid Mazroui, John Richardson, Jerry Pelletier and Imed Eddine Gallouzi ()
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Sergio Di Marco: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Anne Cammas: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Xian Jin Lian: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Erzsebet Nagy Kovacs: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Jennifer F. Ma: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Derek T. Hall: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Rachid Mazroui: Departement de Biologie moléculaire, biochimie médicale et pathologie, Centre de Recherche Hôpital Saint-François d'Assise
John Richardson: McGill University, 3801 University Street, Montreal, Quebec, Canada H3A2B4.
Jerry Pelletier: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler
Imed Eddine Gallouzi: Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract Cachexia, or muscle-wasting syndrome, is one of the major causes of death in patients affected by diseases such as cancer, AIDS and sepsis. However, no effective anti-cachectic treatment is currently available. Here we show that a low dose of pateamine A, an inhibitor of translation initiation, prevents muscle wasting caused by the cytokines interferon γ and tumour necrosis factor α or by C26-adenocarcinoma tumours. Surprisingly, although high doses of pateamine A abrogate general translation, low doses selectively inhibit the expression of pro-cachectic factors such as inducible nitric oxide synthase. This selectivity depends on the 5′UTR of inducible nitric oxide synthase messenger RNA (mRNA) that, unlike the 5′UTR of MyoD mRNA, promotes the recruitment of inducible nitric oxide synthase mRNA to stress granules, where its translation is repressed. Collectively, our data provide a proof of principle that nontoxic doses of compounds such as pateamine A could be used as novel drugs to combat cachexia-induced muscle wasting.

Date: 2012
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DOI: 10.1038/ncomms1899

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