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

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.

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…This effect was proposed to be the result of selective sequestration of cachetic-promoting mRNAs into stress granules. As such, among mRNAs found within PatA-induced stress granules include inducible nitric oxide synthase (iNOS), a key effector in NF-κB-mediated muscle-wasting that promotes inflammation and degradation of mRNAs associated with muscle maintenance, such as MyoD and myogenin [132]. The selectivity of sequestration is suggested to be mediated by features within the mRNA 5′ UTR, although it is unknown as to which elements would influence this differential effect.…”

“…Additionally, sub-cytotoxic concentrations of PatA have been recently found to be protective against cachexia-induced muscle wasting [132]. One characteristic feature of muscle wasting is repression of global translation and unexpectedly, low doses of PatA partially reversed this inhibition [132].…”

“…One characteristic feature of muscle wasting is repression of global translation and unexpectedly, low doses of PatA partially reversed this inhibition [132]. This effect was proposed to be the result of selective sequestration of cachetic-promoting mRNAs into stress granules.…”

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

“…C26 tumor-bearing mice are widely used to study cancer cachexia [19][20][21]. The C26 cells were cultured in a humidified 5% CO 2 incubator using RPMI 1640 supplemented with 1% penicillin/streptomycin (vol/vol) and 10% FBS (vol/vol).…”

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

“…In up to 30% of all cancers it leads to death through a combination of extreme weakness, decreased resistance to infection, and the inability to tolerate needed therapy (1)(2)(3). Cachexia is especially prevalent in cancers of the colon, lung, and pancreas and involves a significant loss of both fat stores and muscle mass throughout the body (1,4).…”