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J. Biol. Chem., Vol. 283, Issue 28, 19748-19756, July 11, 2008

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Myosin Regulatory Light Chain Phosphorylation Attenuates Cardiac Hypertrophy^*

Jian Huang, John M. Shelton, James A. Richardson^¶||, Kristine E. Kamm, and James T. Stull¹

From the Departments of Physiology, Internal Medicine, ^¶Pathology, and ^||Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Hyperphosphorylation of myosin regulatory light chain (RLC) in cardiac muscle is proposed to cause compensatory hypertrophy. We therefore investigated potential mechanisms in genetically modified mice. Transgenic (TG) mice were generated to overexpress Ca²⁺/calmodulin-dependent myosin light chain kinase specifically in cardiomyocytes. Phosphorylation of sarcomeric cardiac RLC and cytoplasmic nonmuscle RLC increased markedly in hearts from TG mice compared with hearts from wild-type (WT) mice. Quantitative measures of RLC phosphorylation revealed no spatial gradients. No significant hypertrophy or structural abnormalities were observed up to 6 months of age in hearts of TG mice compared with WT animals. Hearts and cardiomyocytes from WT animals subjected to voluntary running exercise and isoproterenol treatment showed hypertrophic cardiac responses, but the responses for TG mice were attenuated. Additional biochemical measurements indicated that overexpression of the Ca²⁺/calmodulin-binding kinase did not perturb other Ca²⁺/calmodulin-dependent processes involving Ca²⁺/calmodulin-dependent protein kinase II or the protein phosphatase calcineurin. Thus, increased myosin RLC phosphorylation per se does not cause cardiac hypertrophy and probably inhibits physiological and pathophysiological hypertrophy by contributing to enhanced contractile performance and efficiency.

Received for publication, April 3, 2008 , and in revised form, May 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL06296 and HL080536. This work was also supported by the Moss Heart Fund and the Fouad A. and Val Imm Bashour Chair in Physiology. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Physiology, 5323 Harry Hines Blvd., UT Southwestern Medical Center, Dallas, TX 75390. Tel.: 214-645-6058; Fax: 214-645-6049; E-mail: james.stull{at}utsouthwestern.edu.

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