癌症惡病質是一種代謝綜合症，其特徵是在癌症患者身上會出現嚴重的骨骼肌 (SKM) 萎縮和脂肪組織消耗。雖然在大多數惡病質的體外實驗中，肌生成調節因子(MRF，其中包括 Myf5、MyoD、MyoG 和 MRF4) 的表達均受到抑制，但在一些研究發現部分患者的惡病質骨骼肌中 MyoG 的表達卻有所增加。我們的初步研究發現，只有在具有嚴重惡病質的 C26 小鼠 (帶有 C26 細胞腫瘤的小鼠) 中 MyoG 表達量顯著增加，而在其他惡病質進展緩慢或輕微的小鼠中並未觀察到此現象，這表明 MyoG 的活化可能僅與嚴重惡病質相關。我們發現，C26 細胞條件培養基 (C26M) 或 RAW264.7 前巨噬細胞條件培養基 (RAWM) 均會抑制肌生成並誘導肌管萎縮，而這種萎縮在 MyoG 過度表達的情況下更加嚴重。有趣的是，MyoG 過度表達卻能逆轉 C26M 所引起的肌生成抑制，這表明 MyoG 在癌症惡病質的發展中扮演了不同的角色。接下來我們克隆了來自不同程度惡病質小鼠的 MyoG 啟動子，並發現了微小的序列差異，此外C26M 抑制了這些啟動子的基礎活性及其被活化的能力，然而來自嚴重惡病質小鼠的 MyoG 啟動子的基礎活性高於其他啟動子。我們還發現 C26M 抑制了 MyoD 對肌生成基因啟動子的轉錄活性，這並非由於 MyoD 蛋白或 mRNA 穩定性的下降所致。綜合來看，我們的研究結果表明，MyoG 的活化僅出現在嚴重惡病質的個體中，並且它在惡病質期間的肌生成抑制和肌肉萎縮中扮演了不同的角色。;Cancer cachexia is a metabolic syndrome characterized by serious skeletal muscle (SKM) and adipose tissues wasting in cancer patients. The expression of myogenic regulatory factors (MRF, including Myf5, MyoD, MyoG, and MRF4) is repressed in most cachexia assay in vitro, but some studies found the expression of MyoG expression was increased in the cachexia SKM of some patients. Our preliminary study found increased MyoG level only in C26 mice (mice carrying C26 cell tumor) with aggressive cachexia but not in others with slow/mild cachexia, suggesting that MyoG activation is associated only with aggressive cachexia. We found that the medium conditioned by either C26 cells (C26M) or RAW264.7 pre-macrophage cells medium (RAWM) could repress myogenesis and induced myotube atrophy, which was aggravated by MyoG over-expression. Ironically, C26M repressed myogenesis was found to be rescued by MyoG over-expression, implying distinct roles of MyoG in the development of cachexia. The promoters of MyoG from mice with different degrees of cachexia were cloned and minor sequence variations were identified, and C26M all repressed their basal and activated activity. However, the basal activity of MyoG promoters from mice with aggressive cachexia was higher than that of other promoters. We also found that the transactivational activity of MyoD on myogenic gene promoters was repressed by C26M, which was not caused reduced MyoD protein and mRNA stability. Taken together, our results suggest that MyoG activation is only found in subjects with aggressive cachexia and it plays distinct roles in repressed myogenesis and atrophy during cachexia.
