The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice
The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice
复制标题
DOI：
10.1038/ncomms1899
复制
发表时间：
2012-06-01
影响因子：
16.6
通讯作者：
Gallouzi, Imed Eddine
中科院分区：
文献类型：
--
作者：
Di Marco, Sergio;Cammas, Anne;Gallouzi, Imed Eddine
恶病质，或肌肉萎缩综合征，是癌症、艾滋病和败血症等疾病患者死亡的主要原因之一。然而，目前还没有有效的抗恶病质治疗方法。在这里，我们证明了小剂量的帕特明A，一种翻译起始的抑制剂，可以防止由细胞因子干扰素和肿瘤坏死因子a或C26腺癌肿瘤引起的肌肉萎缩。令人惊讶的是，尽管高剂量的帕特明A取消了一般的翻译，但低剂量选择性地抑制了促恶病质因子的表达，如诱导型一氧化氮合酶。这种选择性取决于诱导型一氧化氮合酶信使RNA(MRNA)的5‘UTR，与MyoD mRNA的5’UTR不同，它促进诱导型一氧化氮合酶mRNA招募到应激颗粒，在那里它的翻译被抑制。总而言之，我们的数据提供了一个原则证据，即无毒剂量的化合物，如帕替胺A，可以用作对抗恶病质引起的肌肉萎缩的新药。
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 gamma and tumour necrosis factor a 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.