pateamine-a and Muscular-Atrophy

Cachexia is a deadly muscle wasting syndrome that arises under conditions linked to chronic inflammation, such as cancer. Cytokines, including interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and their downstream effectors such as Signal Transducer and Activator of Transcription 3 (STAT3), have been shown to play a prominent role in muscle wasting. Previously, we demonstrated that Pateamine A (PatA), a compound that targets eukaryotic initiation factor 4A (eIF4A), could prevent muscle wasting by modulating the translation of the inducible Nitric Oxide Synthase (iNOS) mRNA. Here we show that hippuristanol, a compound that impedes eIF4A in a manner distinct from PatA, similarly inhibits the iNOS/NO pathway and cytokine-induced muscle wasting. Furthermore, we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3-gene targets such as IL-6. The decreased activation of STAT3, which resulted from a decrease in STAT3 protein expression, was due to the inhibition of STAT3 translation as there were no changes in STAT3 mRNA levels. These effects are likely dependent on the inhibition of eIF4A activity since we observed similar results using PatA. Our results identify the inhibition of eIF4A-responsive transcripts, such as STAT3, as a viable approach to alleviate cachexia.

Topics: Allosteric Regulation; Animals; Cell Line; Cytokines; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Interleukin-6; Macrolides; Mice; Muscle Fibers, Skeletal; Muscular Atrophy; Nitric Oxide Synthase Type II; STAT3 Transcription Factor; Sterols; Thiazoles

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.

Topics: Animals; Apoptosis; Blotting, Northern; Cachexia; Cell Line; Epoxy Compounds; Immunoblotting; Immunoprecipitation; In Situ Hybridization; Interleukin-6; Macrolides; Male; Mice; Mice, Inbred BALB C; Muscular Atrophy; Nitrogen Oxides; Thiazoles