Cachexia or muscle-wasting syndrome is one of the major causes of death in patients affected by diseases such as cancer AIDS and sepsis. 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. Cachexia characterized by excessive weight loss and skeletal muscle deterioration (muscle wasting) is a disorder that often affects individuals with cancer AIDS chronic obstructive pulmonary disease and sepsis1 2 These individuals lose skeletal muscle mass owing to a decreased rate of synthesis and enhanced degradation of muscle proteins. Cancer patients affected by cachexia experience a lower quality of life and respond more poorly to therapy and ~30% of all cancer-related deaths are the direct result of cachexia-induced muscle wasting1 2 Despite the fact that Cachexia and its consequences have been known for decades there are no effective treatments to prevent its onset and/or progression. Although the symptoms of cachexia are diverse several key mediators have been identified. Pro-inflammatory cytokines such as interferon γ (IFNγ) and tumour necrosis factor α (TNFα) have been shown to induce muscle wasting in individuals affected with cancer or chronic inflammation3 4 5 The ability of both IFNγ and TNFα to induce muscle wasting Tazarotenic acid is mediated by the activation of the transcription factor NF-κB5 6 One of the main consequences of activating the NF-κB pathway in muscle fibres is the decreased expression of key factors required for the formation and maintenance of muscle fibres such as MyoD Myogenin and the myosin heavy chain (MyHC)5 6 7 Furthermore induction of the NF-κB pathway enhances the expression of the E3 ligase MURF1 which in turn activates the ubiquitin-proteasome pathway resulting in the degradation of proteins during muscle wasting8 9 One of the principal effectors of NF-κB-mediated muscle wasting is nitric oxide (NO) a gas normally secreted by cells to defend against pathogenic infections2 6 10 NO is produced as a result of the conversion of L-arginine to citrulline by enzymes such as inducible NO Synthase (iNOS)11. NO mediates several of the deleterious consequences associated with an aggravated pro-inflammatory response including cytokine-induced muscle wasting1 6 12 Indeed treatment of muscle cells with IFNγ and TNFα stimulates in an NF-κB-dependent manner the expression of iNOS and Tazarotenic acid subsequently the secretion of NO6 10 The importance of NO in muscle wasting was demonstrated using an iNOS inhibitor which prevented the onset of muscle loss and the subsequent death of animals that occurred on induction of cachexia13. Moreover the NF-κB-induced decrease in MyoD messenger RNA levels in muscle Tazarotenic acid fibres is mediated by the iNOS/NO pathway6. These results therefore suggest that targeting the iNOS/NO pathway could prove to be an effective treatment option to prevent cachexia-induced muscle wasting. Compounds HSP27 known to inhibit eukaryotic initiation of translation possess anti-tumorigenic and immunosuppressive properties14 15 Recently compounds such as Pateamine A (PatA isolated from the marine sponge and This effect is mediated by a novel and unexpected mechanism through which PatA while inhibiting iNOS mRNA translation in a 5′UTR-dependent manner promotes the expression of MyoD and Myogenin. Our result also show that the inhibition of iNOS translation by PatA is likely due to an increased association of its mRNA to eIF4A and the accumulation of iNOS mRNA/eIF4A complex in Tazarotenic acid SGs. Our data suggest that Tazarotenic acid these small molecules could be used as a novel strategy to combat the onset and progression of cachexia. Results Pateamine A blocks cytokine-induced muscle wasting PatA prevents in a dose-dependent manner the proliferation of cancer cells by inhibiting DNA synthesis during the phase of the cell cycle31. Because myogenesis (the process of muscle fibre formation) requires the cell cycle arrest of myoblasts (embryonic muscle cells)32 we verified the effect of PatA on this process. C2C12 an established muscle cell Tazarotenic acid line33 was induced to differentiate for 4 days in the presence or absence of different doses of PatA..