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J. Biol. Chem., Vol. 283, Issue 29, 20484-20494, July 18, 2008

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Functional Consequences of the Human Cardiac Troponin I Hypertrophic Cardiomyopathy Mutation R145G in Transgenic Mice^*

Yuhui Wen, Jose Renato Pinto, Aldrin V. Gomes^¶, Yuanyuan Xu, Yingcai Wang, Ying Wang, James D. Potter¹², and W. Glenn L. Kerrick¹

From the Department of Physiology and Biophysics and Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136 and the ^¶Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616

In this study, we addressed the functional consequences of the human cardiac troponin I (hcTnI) hypertrophic cardiomyopathy R145G mutation in transgenic mice. Simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145G transgenic mice (Tg-R145G) versus hcTnI wild type transgenic mice (Tg-WT) showed a significant decrease in the maximal Ca²⁺-activated force without changes in the maximal ATPase activity and an increase in the Ca²⁺ sensitivity of both ATPase and force development. No difference in the cross-bridge turnover rate was observed at the same level of cross-bridge attachment (activation state), showing that changes in Ca²⁺ sensitivity were not due to changes in cross-bridge kinetics. Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared with Tg-WT fibers. The addition of 3 mM 2,3-butanedione monoxime at pCa 9.0 showed that there was 2-4% of force generating cross-bridges attached in Tg-R145G fibers compared with less than 1.0% in Tg-WT fibers, suggesting that the mutation impairs the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions. Prolonged force and intracellular [Ca²⁺] transients in electrically stimulated intact papillary muscles were observed in Tg-R145G compared with Tg-WT. These results suggest that the phenotype of hypertrophic cardiomyopathy is most likely caused by the compensatory mechanisms in the cardiovascular system that are activated by 1) higher energy cost in the heart resulting from a significant decrease in average force per cross-bridge, 2) slowed relaxation (diastolic dysfunction) caused by prolonged [Ca²⁺] and force transients, and 3) an inability of the cardiac TnI to completely inhibit activation in the absence of Ca²⁺ in Tg-R145G mice.

Received for publication, February 29, 2008 , and in revised form, April 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL-67415 and HL-42325. 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 Joint senior authors who contributed equally to this work.

² To whom correspondence should be addressed: 1600 N.W. 10th Ave. (R-189), Miami, FL 33136. Tel.: 305-243-5874; Fax: 305-324-6024; E-mail: jdpotter{at}miami.edu.

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