Myoblast differentiation is fundamental to the development and regeneration of skeletal muscle after injury or disease. MyoD family transcription factors play a key role to promote myoblast differentiation. In a screen for MyoD activators, we identified tetrahydropalmatine (THP), a natural compound isolated from Corydalis turtschaninovii. The treatment of C2C12 myoblasts with THP enhanced the level of MyoD, Myogenin and myosin heavy chain (MHC) proteins and the formation of larger multinucleated myotubes, compared to the control treatment. The THP treatment dramatically enhanced the activities of p38MAPK and Akt, the key promyogenic kinases which activate MyoD. The enhanced myoblast differentiation by THP treatment can be blocked by inhibition of p38MAPK or Akt by SB203580 or LY294002, respectively. In addition, THP treatment restored myotube formation of Cdo-depleted C2C12 cells through activation of p38MAPK. Moreover, THP enhanced the efficiency of trans-differentiation of 10T1/2 fibroblasts into myoblasts mediated by MyoD. These results indicate that THP has a promyogenic effect by upregulation of p38MAPK and Akt resulting in enhanced MyoD activation. Our findings suggest that THP has a potential as a therapeutic candidate to prevent fibrosis and improve muscle regeneration and repair. (C) 2014 Elsevier Inc. All rights reserved.