The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice.
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.
Department of Biochemistry, Rosalind and Morris Goodman Cancer Center, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada.
Sergio
S
Di Marco
Anne
A
Cammas
Xian Jin
XJ
Lian
Erzsebet Nagy
EN
Kovacs
Jennifer F
JF
Ma
Derek T
DT
Hall
Rachid
R
Mazroui
John
J
Richardson
Jerry
J
Pelletier
Imed Eddine
IE
Gallouzi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D002100:Cachexia / Q000503:physiopathology*; D002460:Cell Line; D004852:Epoxy Compounds / Q000627:therapeutic use*; D015151:Immunoblotting; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000378:metabolism; D018942:Macrolides / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*
D004852:Epoxy Compounds; D015850:Interleukin-6; D018942:Macrolides; D009589:Nitrogen Oxides; D013844:Thiazoles; C421324:pateamine A