Transcription activation of myostatin by trichostatin A in differentiated C2C12 myocytes via ASK1‐MKK3/4/6‐JNK and p38 mitogen‐activated protein kinase pathways

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 C2C12 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 C2C12 myoblasts. The protein levels of phosphorylated p38 MAPK, JNK, but not ERK, increased with TSA treatment in differentiated C2C12 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 C2C12 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.

[1]  Ya-Yun Cheng,et al.  Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions , 2009, Nucleic acids research.

[2]  Chulhee Choi,et al.  Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1 , 2009, Cardiovascular research.

[3]  S. Hatakeyama,et al.  Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. , 2009, American journal of physiology. Cell physiology.

[4]  Eric Chevet,et al.  Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer , 2008, Pharmacological Reviews.

[5]  C. Lowenstein,et al.  Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling , 2008, The Journal of experimental medicine.

[6]  Christophe Marcelle,et al.  Myostatin promotes the terminal differentiation of embryonic muscle progenitors. , 2008, Genes & development.

[7]  M. Rudnicki,et al.  Satellite and stem cells in muscle growth and repair , 2007, Development.

[8]  F. Haddad,et al.  Combined isometric, concentric, and eccentric resistance exercise prevents unloading-induced muscle atrophy in rats. , 2007, Journal of applied physiology.

[9]  R. Casaburi,et al.  Exercise in maintenance hemodialysis patients induces transcriptional changes in genes favoring anabolic muscle. , 2007, Journal of the American Society of Nephrology : JASN.

[10]  K. Storey,et al.  p38MAPK regulation of transcription factor targets in muscle and heart of the hibernating bat, Myotis lucifugus , 2007, Cell biochemistry and function.

[11]  Daiwen Chen,et al.  Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells. , 2007, Cellular signalling.

[12]  P. Marks,et al.  Histone Deacetylase Inhibitors: Overview and Perspectives , 2007, Molecular Cancer Research.

[13]  P. Marks,et al.  Histone deacetylase inhibitors: molecular mechanisms of action , 2007, Oncogene.

[14]  B. Pace,et al.  Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2. , 2006, Blood.

[15]  Kevin K. Yang,et al.  Apoptosis Signal-regulating Kinase 1 Is a Direct Target of E2F1 and Contributes to Histone Deacetylase Inhibitorinduced Apoptosis through Positive Feedback Regulation of E2F1 Apoptotic Activity* , 2006, Journal of Biological Chemistry.

[16]  Wei-Guo Zhu,et al.  Acetylation of p53 at Lysine 373/382 by the Histone Deacetylase Inhibitor Depsipeptide Induces Expression of p21Waf1/Cip1 , 2006, Molecular and Cellular Biology.

[17]  C. Hsieh,et al.  Thioredoxin‐ASK1 complex levels regulate ROS‐mediated p38 MAPK pathway activity in livers of aged and long‐lived Snell dwarf mice , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  Yan Chen,et al.  Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway is involved in myostatin-regulated differentiation repression. , 2006, Cancer research.

[19]  Donglei Zhang,et al.  Expression of myostatin RNA transcript and protein in gastrocnemius muscle of rats after sciatic nerve resection , 2006, Journal of Muscle Research & Cell Motility.

[20]  Wei-Shiung Yang,et al.  Insulin-like growth factor-1 mediates stretch-induced upregulation of myostatin expression in neonatal rat cardiomyocytes. , 2005, Cardiovascular research.

[21]  Kunihiro Matsumoto,et al.  ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity , 2005, Nature Immunology.

[22]  K. Venkatasubbarao,et al.  Trichostatin A Induces Transforming Growth Factor β Type II Receptor Promoter Activity and Acetylation of Sp1 by Recruitment of PCAF/p300 to a Sp1·NF-Y Complex* , 2005, Journal of Biological Chemistry.

[23]  Zhijian Lu,et al.  Regulation of GDF-8 signaling by the p38 MAPK. , 2005, Cellular signalling.

[24]  S. Bhasin,et al.  Role of myostatin in metabolism , 2004, Current opinion in clinical nutrition and metabolic care.

[25]  E. Seto,et al.  Activation of the Growth-Differentiation Factor 11 Gene by the Histone Deacetylase (HDAC) Inhibitor Trichostatin A and Repression by HDAC3 , 2004, Molecular and Cellular Biology.

[26]  B. Langley,et al.  Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway , 2004, Oncogene.

[27]  Nathan Salomonis,et al.  Time- and exercise-dependent gene regulation in human skeletal muscle , 2003, Genome Biology.

[28]  V. Paralkar,et al.  Myostatin expression in age and denervation-induced skeletal muscle atrophy. , 2003, Journal of musculoskeletal & neuronal interactions.

[29]  O. Witt,et al.  Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. , 2003, Blood.

[30]  J. Oldham,et al.  Prolonged underfeeding of sheep increases myostatin and myogenic regulatory factor Myf-5 in skeletal muscle while IGF-I and myogenin are repressed. , 2003, The Journal of endocrinology.

[31]  Changlong Li,et al.  P27 knockout mice: reduced myostatin in muscle and altered adipogenesis. , 2003, Biochemical and biophysical research communications.

[32]  R. Ahima,et al.  Functional improvement of dystrophic muscle by myostatin blockade , 2002, Nature.

[33]  F. Jeanplong,et al.  The Myostatin Gene Is a Downstream Target Gene of Basic Helix-Loop-Helix Transcription Factor MyoD , 2002, Molecular and Cellular Biology.

[34]  A. Khurana,et al.  Subtype specific roles of mitogen activated protein kinases in L6E9 skeletal muscle cell differentiation , 2002, Molecular and Cellular Biochemistry.

[35]  Chun Li Zhang,et al.  Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy , 2002, Cell.

[36]  T. Zimmers,et al.  Induction of Cachexia in Mice by Systemically Administered Myostatin , 2002, Science.

[37]  S. Bhasin,et al.  Characterization of 5'-regulatory region of human myostatin gene: regulation by dexamethasone in vitro. , 2001, American journal of physiology. Endocrinology and metabolism.

[38]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[39]  E. Olson,et al.  Control of muscle development by dueling HATs and HDACs. , 2001, Current opinion in genetics & development.

[40]  C. Lang,et al.  Regulation of Myostatin by Glucocorticoids After Thermal Injury , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  R. Schiltz,et al.  A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program , 2001, The EMBO journal.

[42]  E. Sausville,et al.  MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells. , 2001, Cancer research.

[43]  R. Tarnuzzer,et al.  Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight. , 2000, The Journal of endocrinology.

[44]  Se-Jin Lee,et al.  Myostatin and the control of skeletal muscle mass. , 1999, Current opinion in genetics & development.

[45]  S. Gordon,et al.  Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[46]  Hengyi Xiao,et al.  Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells , 1999, Journal of cellular biochemistry.

[47]  P. Anderson,et al.  Trichothecene Mycotoxins Trigger a Ribotoxic Stress Response That Activates c-Jun N-terminal Kinase and p38 Mitogen-activated Protein Kinase and Induces Apoptosis* , 1999, The Journal of Biological Chemistry.

[48]  Kohei Miyazono,et al.  Mammalian thioredoxin is a direct inhibitor of apoptosis signal‐regulating kinase (ASK) 1 , 1998, The EMBO journal.

[49]  S. Keyse.  Protein phosphatases and the regulation of MAP kinase activity. , 1998, Seminars in cell & developmental biology.

[50]  Se-Jin Lee,et al.  Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member , 1997, nature.

[51]  C. Tachi,et al.  Content and localization of myostatin in mouse skeletal muscles during aging, mechanical unloading and reloading , 2004, Journal of Muscle Research & Cell Motility.

[52]  C. Van Lint,et al.  The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. , 1996, Gene expression.

[53]  John C. Schug,et al.  Tess: transcription element search software on the www , 1977 .

[54]  Thomas D. Schmittgen,et al.  Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 2 DD C T Method , 2022 .