Identification of Map4k4 as a Novel Suppressor of Skeletal Muscle Differentiation

• DOI: 10.1128/mcb.00618-12
• Publication Date: 2012-12-04T15:43:41Z
• Authors: Mengxi Wang; Shinya U. Amano; Rachel J. Roth Flach; Anil Chawla; Myriam Aouadi; Michael P. Czech
• Keywords: MYF5; C2C12

Myoblast differentiation into mature myotubes is a critical step in the development and repair of human skeletal muscle. Here we show that small interfering RNA (siRNA)-based silencing Ste20-like mitogen-activated protein 4 kinase (Map4k4) C2C12 myoblasts markedly enhances expression myogenic genes, myoblast fusion, myotube diameter. In contrast, adenovirus-mediated native Map4k4 cells attenuates each these processes, indicating negative regulator hypertrophy. Expression kinase-inactive mutant formation, suggesting activity essential for its inhibition muscle differentiation. regulation myogenesis unlikely to be mediated by classic (MAPK) signaling pathways, because no significant difference phosphorylation extracellular signal-regulated (ERK), p38, or c-Jun N-terminal (JNK) observed Map4k4-silenced cells. Furthermore, other MAPKs does not result hypertrophic phenotype like seen with depletion. Uniquely, upregulates regulatory factor Myf5, whose depletion inhibits myogenesis. Myf5 required enhancement formation cells, while overexpression rescues Map4k4-mediated These results demonstrate novel suppressor differentiation, acting through Myf5-dependent mechanism.