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J. Biol. Chem., Vol. 280, Issue 44, 37183-37194, November 4, 2005

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F110I and R278C Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy Affect Muscle Contraction in Transgenic Mice and Reconstituted Human Cardiac Fibers^*

Olga M. Hernandez, Danuta Szczesna-Cordary, Björn C. Knollmann, Todd Miller, Michael Bell¶, Jiaju Zhao, Syevda G. Sirenko, Zoraida Diaz, Georgianna Guzman, Yuanyuan Xu||, Ying Wang||, W. Glenn L. Kerrick||, and James D. Potter1

From the Department of Pharmacology, Georgetown University Medical Center, Washington, D. C. 20057 and the Departments of Molecular and Cellular Pharmacology, ^||Physiology and Biophysics, and ^¶Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136

We have studied the physiological effects of the troponin T (TnT) F110I and R278C mutations associated with familial hypertrophic cardiomyopathy (FHC) in humans. Three to four-month-old transgenic (Tg) mice expressing F110I-TnT and R278C-TnT did not develop significant hypertrophy or ventricular fibrosis even after chronic exercise challenge. The F110I mutation impaired acute exercise tolerance, whereas R278C did not. Skinned papillary muscle fibers from transgenic mice expressing F110I-TnT demonstrated increased Ca²⁺ sensitivity of force and ATPase activity, and likewise an increased Ca²⁺ sensitivity of force was observed in F110I-TnT-reconstituted human cardiac muscle preparations. In contrast, no changes in force or the ATPase-pCa dependencies were observed in transgenic R278C fibers or in human fibers reconstituted with the R278C-TnT mutant. The maximal level of force development was dramatically decreased in both transgenic mice. However, the maximal ATPase was not different (R278C-TnT) or only slightly less (F110I-TnT) than that of non-Tg and WT-Tg littermates. Consequently, their ratios of ATPase/force (energy cost) at all Ca²⁺ concentrations were dramatically higher compared with non-Tg and WT-Tg fibers. This increase in energy cost most likely results from a decrease in force per myosin cross-bridge, because forcing all cross-bridges into the force generating state by substitution of MgADP for MgATP in maximum contracting solutions resulted in the same increase in maximal force (15%) in all transgenic and non-transgenic preparations. The combination of increased Ca²⁺ sensitivity and energy cost in the F110I hearts may be responsible for the greater severity of this phenotype compared with the R278C mutation.

Received for publication, July 25, 2005 , and in revised form, August 22, 2005.

^* This work was supported by National Institutes of Health Grants HL42325 and HL67415 (to J. D. P.), National Institutes of Health Grant HL071778 (to D. S-C.), and National Institutes of Health Grants HL071670 (to B. C. K.) and AHA-0120319B (to O. M. H.). 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: Dept. of Molecular and Cellular Pharmacology, University of Miami School of Medicine, 1600 N.W. 10th Ave., Miami, FL 33136. Tel.: 305-243-5874; Fax: 305-324-6024; E-mail: jdpotter{at}miami.edu.

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