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J. Biol. Chem., Vol. 283, Issue 15, 10135-10146, April 11, 2008

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HDAC4 and PCAF Bind to Cardiac Sarcomeres and Play a Role in Regulating Myofilament Contractile Activity^*

Mahesh P. Gupta¹, Sadhana A. Samant, Stephen H. Smith, and Sanjeev G. Shroff

From the Department of Surgery, Committee on Molecular Medicine, Biological Science Division, University of Chicago, Chicago, Illinois 60637 and the Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Reversible acetylation of lysine residues within a protein is considered a biologically relevant modification that rivals phosphorylation ( Kouzarides, T. (2000) EMBO J. 19, 1176-1179[CrossRef][Medline] [Order article via Infotrieve] ). The enzymes responsible for such protein modification are called histone acetyltransferases (HATs) and deacetylases (HDACs). A role of protein phosphorylation in regulating muscle contraction is well established ( Solaro, R. J., Moir, A. J., and Perry, S. V. (1976) Nature 262, 615-617[CrossRef][Medline] [Order article via Infotrieve] ). Here we show that reversible protein acetylation carried out by HATs and HDACs also plays a role in regulating the myofilament contractile activity. We found that a Class II HDAC, HDAC4, and an HAT, PCAF, associate with cardiac myofilaments. Primary cultures of cardiomyocytes as well as mouse heart sections examined by immunohistochemical and electron microscopic analyses revealed that both HDAC4 and PCAF associate with the Z-disc and I- and A-bands of cardiac sacromeres. Increased acetylation of sarcomeric proteins by HDAC inhibition (using class I and II HDAC inhibitors or anti-HDAC4 antibody) enhanced the myofilament calcium sensitivity. We identified the Z-disc-associated protein, MLP, a sensor of cardiac mechanical stretch, as an acetylated target of PCAF and HDAC4. We also show that trichostatin-A, a class I and II HDAC inhibitor, increases myofilament calcium sensitivity of wild-type, but not of MLP knock-out mice, thus demonstrating a role of MLP in acetylation-dependent increased contractile activity of myofilaments. These studies provide the first evidence that HATs and HDACs play a role in regulation of muscle contraction.

Received for publication, December 18, 2007 , and in revised form, January 24, 2008.

^* This work was supported in part by National Institutes of Health Grants RO1 HL-68083, HL-77788, and HL83423 and McGinnis Endowed Chair funds. 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.

¹ To whom correspondence should be addressed: 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-834-7811; E-mail: mgupta{at}surgery.bsd.uchicago.edu.

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