MyoD and Myogenin regulatory cascade is targeted by tumor signals to repress myogenesis in cancer cachexia

It is estimated that about 20-30% cancer death is directly linked to the syndrome called cancer cachexia (CAC), which is characterized by debilitating skeletal muscle (SKM) and fat wasting. Recent studies have found that the myogenic ability of myogenic stem cells (MuSC) in the cachectic SKM is compromised, but the mechanisms remain to be clarified. Using the C26 colon cancer cells mediated cachexia model, the down-regulation of myogenic regulatory factors (MRF) MyoD and MyoG, but not Myf5 and Mrf4, was confirmed in vitro and in vivo. We further found the repression of myogenesis by C26 cells conditioned medium (C26M) in vitro could be rescued by inducible over-expression of either MyoD or MyoG, but not Myf5 or Mrf4. As MyoD is the major upstream activator of MyoG, these findings suggest the targeting of the MyoD-MyoG regulatory cascade by CAC signals. The transactivation of myogenic gene promoters by MyoD was also constantly repressed by C26M, suggesting MyoD dysfunction is critical to myogenesis repression in CAC. The repression of MyoD gene transcription by C26M was found to be mediated by the core enhancer (CE) located in the distal enhancer (DE) region. The activation of CE mediated promoter activity by MyoD, ß-Catenin*, and Pbx1 was significantly reduced by C26M, implying the repression of MyoD positive feedback loop. Taken together, these observations suggest that CAC signals repress both MyoD transactivational activity on target genes and its transcriptional activation by upstream activators, which subsequently leads to repression of myogenesis and failed regeneration in cachectic SKM.