Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice.

Proinflammatory cytokines contribute to the progression of muscle wasting caused by ubiquitin-proteasome-dependent proteolysis. We have previously demonstrated that isoflavones, such as genistein and daidzein, prevent TNF-α-induced muscle atrophy in C2C12 myotubes. In this study, we examined the effect of dietary flavonoids on the wasting of muscle. Mice were divided into the following four groups: vehicle-injected (control) mice fed the normal diet (CN); tumor-bearing mice fed the normal diet (TN); control mice fed the isoflavone diet (CI); and tumor-bearing mice fed the isoflavone diet (TI). There were no significant differences in the intake of food or body weight gain among these four groups. The wet weight and myofiber size of gastrocnemius muscle in TN significantly decreased, compared with those in CN. Interestingly, the wet weight and myofiber size of gastrocnemius muscle in TI were nearly the same as those in CN and CI, although isoflavone supplementation did not affect the increased tumor mass or concentrations of proinflammatory cytokines, such as TNF-α and IL-6, in the blood. Moreover, increased expression of muscle-specific ubiquitin ligase genes encoding MAFbx/Atrogin-1 and MuRF1 in the skeletal muscle of TN was significantly inhibited by the supplementation of isoflavones. In parallel with the expression of muscle-specific ubiquitin ligases, dietary isoflavones significantly suppressed phosphorylation of ERK in tumor-bearing mice. These results suggest that dietary isoflavones improve muscle wasting in tumor-bearing mice via the ERK signaling pathway mediated-suppression of ubiquitin ligases in muscle cells.

The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22.

We analysed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. MYO1F consists of at least 28 exons and was predicted to encode a 1098-amino-acid with an N-terminal head domain containing both ATP-binding and actin-binding sequences, a neck domain with a single IQ motif, and a tail with TH1, TH2 and SH3 domains. Northern blot analysis of RNAs prepared from multiple tissues showed that the expression of approximately 4-kb transcripts appeared constant in most tissues examined. However, MYO1F was expressed in only three of 22 leukemic cell lines. The MLL-MYO1F fusion protein contains almost the entire MYO1F, however, C-terminal MYO1F has neither the transactivation domain nor the dimerization domain found in various MLL fusion partners. Further analysis of this novel type of MLL fusion protein would provide new insights into leukemogenesis. MYO1F is the fourth partner gene of MLL on 19p13. At the cytogenetic level, it may be difficult to distinguish MLL-ENL, MLL-ELL, MLL-EEN and MLL-MYO1F fusions created by t(11;19)(q23;p13), and it is likely that cases of t(11;19) lacking a known fusion gene may result in this gene fusion.