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J. Biol. Chem., Vol. 282, Issue 10, 7265-7275, March 9, 2007

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The p38/ Mitogen-activated Protein Kinases Mediate Recruitment of CREB-binding Protein to Preserve Fast Myosin Heavy Chain IId/x Gene Activity in Myotubes^*

Joachim D. Meissner¹, Kin-Chow Chang, Hans-Peter Kubis², Angel R. Nebreda^¶, Gerolf Gros, and Renate J. Scheibe^||

From the Departments of Physiology and ^||Biochemistry, Hannover Medical School, D-30625 Hannover, Germany, the Division of Animal Production & Public Health, University of Glasgow Veterinary School, G61 1QH Glasgow, United Kingdom, and the ^¶CNIO (Spanish National Cancer Centre), 28029 Madrid, Spain

In skeletal muscle, the transformation of fast into slow fiber type is accompanied by shifts in fiber type-specific gene expression that includes down-regulation of the adult fast fiber myosin heavy chain IId/x (MyHCIId/x) gene. Here, we report that the mitogen-activated protein kinases (MAPKs) p38/ regulate MyHCIId/x gene expression. Electrical stimulation of rabbit skeletal muscle cells with a slow fiber type activity pattern and treatment of C2C12 myotubes with Ca²⁺-ionophore inhibited p38/ MAPKs and reduced fast fiber type MyHC protein expression and promoter activity. Pharmacological inhibition of p38/ also down-regulated MyHCII gene expression. In controls, binding of the myocyte enhancer factor-2 (MEF-2) isoforms C and D as a heterodimer to a proximal consensus site within the MyHCIId/x promoter and recruitment of a transcriptional coactivator, the CREB-binding protein CBP, were observed. Overexpression of wild type MEF-2C but not of a MEF-2C mutant that cannot be phosphorylated by p38 induced promoter activity. Mutation of the MEF-2-binding site decreased the inducing effect of overexpressed CBP. Inhibition of p38/ MAPKs abolished CBP binding, whereas enforced induction of p38 by activated MAPK kinase 6 (MKK6EE) enhanced binding of CBP and increased promoter activity. Furthermore, knockdown of endogenous CBP by RNA interference eliminated promoter activation by MEF-2C or MKK6EE. In electrical stimulated and Ca²⁺-ionophore-treated myotubes, CBP was absent in complex formation at that site. Taken together, the data indicate that p38/ MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle.

Received for publication, September 25, 2006 , and in revised form, December 13, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants GR489/13 and GR489/20. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: School of Sport, Health and Exercise Sciences, University of Wales, Bangor, UK.

¹ To whom correspondence should be addressed: Dept. of Physiology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel.: 49-511-532-2753; Fax: 49-511-532-2938; E-mail: meissner.joachim{at}mh-hannover.de.

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