Transcription activation of myostatin by trichostatin A in differentiated C2C12 myocytes via ASK1-MKK3/4/6-JNK and p38 mitogen-activated protein kinase pathways
✍ Scribed by Der-Sheng Han; Hsiang-Po Huang; Tyng-Guey Wang; Meng-Yu Hung; Jia-Yu Ke; Kuei-Ting Chang; Hsin-Yu Chang; Yu-Ping Ho; Wei-Yuan Hsieh; Wei-Shiung Yang
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 433 KB
- Volume
- 111
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Abstract
Myostatin is a negative regulator of skeletal muscle mass. The pathways employed in modulating myostatin gene expression are scarcely known. We aimed to determine the signaling pathway of myostatin induction by a histone deacetylase (HDAC) inhibitor–trichostatin A (TSA) in differentiated C~2~C~12~ myocytes. TSA increased myostatin mRNA expression up to 40‐fold after treatment for 24 h, and induced myostatin promoter activity up to 3.8‐fold. Pretreatment with actinomycin D reduced the TSA‐induced myostatin mRNA by 93%, suggesting TSA‐induced myostatin expression mainly at the transcriptional level. Pretreatment with p38 MAPK (SB203580) and JNK (SP600125) inhibitors, but not ERK (PD98059) inhibitor, blocked TSA‐induced myostatin expression, respectively, by 72% and 43%. Knockdown of p38 MAPK by RNAi inhibited the TSA‐induced myostatin expression by 77% in C~2~C~12~ myoblasts. The protein levels of phosphorylated p38 MAPK, JNK, but not ERK, increased with TSA treatment in differentiated C~2~C~12~ cells. Direct activation of p38 MAPK and JNK by anisomycin in the absence of TSA increased myostatin mRNA by fourfold. The phosphorylated form of the kinase MKK3/4/6 and ASK1, upstream cascades of p38 MAPK and JNK, also increased with TSA treatment. We concluded that the induction of myostatin by TSA treatment in differentiated C~2~C~12~ cells is in part through ASK1‐MKK3/6‐p38 MAPK and ASK1‐MKK4‐JNK signaling pathways. Activation of p38 MAPK and JNK axis is necessary, but not sufficient for TSA‐induced myostatin expression. J. Cell. Biochem. 111: 564–573, 2010. © 2010 Wiley‐Liss, Inc.