Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells.
Myostatin, a member of the transforming growth factor beta (TGF-beta) superfamily, is a negative regulator of skeletal muscle growth. We found that myostatin could activate c-Jun N-terminal kinase (JNK) signaling pathway in both proliferating and differentiating C2C12 cells. Using small interfering RNA (siRNA) mediated activin receptor type IIB (ActRIIB) knockdown, the myostatin-induced JNK activation was significantly reduced, indicating that ActRIIB was required for JNK activation by myostatin. Transfection of C2C12 cells with TAK1-specific siRNA reduced myostatin-induced JNK activation. In addition, JNK could not be activated by myostatin when the expression of MKK4 was suppressed with MKK4-specific siRNA, suggesting that TAK1-MKK4 cascade was involved in myostatin-induced JNK activation. We also found that blocking JNK signaling pathway by pretreatment with JNK specific inhibitor SP600125, attenuated myostatin-induced upregulation of p21 and downregulation of the differentiation marker gene expression. Furthermore, it was also observed that the presence of SP600125 almost annulled the growth inhibitory role of myostatin. Our findings provide the first evidence to reveal the involvement of JNK signaling pathway in myostatin's function as a negative regulator of muscle growth.
Huang
Zhiqing
Z
Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan, PR China.
Chen
Daiwen
D
Zhang
Keying
K
Yu
Bing
B
Chen
Xiaoling
X
Meng
Jianghong
J
D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology*; D055435:Myostatin; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D030301:Activin Receptors, Type II; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D055435:Myostatin; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C525912:Mstn protein, mouse; C425584:activin receptor type II-B