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J. Biol. Chem., Vol. 281, Issue 40, 29575-29582, October 6, 2006

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Alterations of Tension-dependent ATP Utilization in a Transgenic Rat Model of Hypertrophic Cardiomyopathy^*

Norbert Frey¹², Klara Brixius¹, Robert H. G. Schwinger^¶, Thomas Benis, Alex Karpowski^||, Hans P. Lorenzen^**, Mark Luedde, Hugo A. Katus, and Wolfgang M. Franz

From the Department of Medicine III, University of Heidelberg, 69120 Heidelberg, Laboratory of Muscle Research and Molecular Cardiology, Clinic III of Internal Medicine, University of Cologne, 50924 Cologne, ^¶Medizinische Klinik II, Klinikum Weiden, 92637 Weiden, the ^||Department of Surgery, University of Hamburg, 20249 Hamburg, the ^**Department of Medicine I, Klinikum Hannover Oststadt, 30659 Hannover, and the Medical Clinic & Policlinic I, Ludwig-Maximilians-University, 81377 Munich, Germany

Although it is established that familial hypertrophic cardiomyopathy (FHC) is caused by mutations in several sarcomeric proteins, including cardiac troponin T (TnT), its pathogenesis is still not completely understood. Previously, we established a transgenic rat model of FHC expressing a human TnT molecule with a truncation mutation (DEL-TnT). This study investigated whether contractile dysfunction and electrical vulnerability observed in DEL-TnT rats might be due to alterations of intracellular Ca²⁺ homeostasis, myofibrillar Ca²⁺ sensitivity, and/or myofibrillar ATP utilization. Simultaneous measurements of the force of contraction and intracellular Ca²⁺ transients were performed in right ventricular trabeculae of DEL-TnT hearts at 0.25 and 1.0 Hz. Rats expressing wild-type human TnT as well as nontransgenic rats served as controls. In addition, calcium-dependent ATPase activity and tension development were investigated in skinned cardiac muscle fibers. Force of contraction was significantly decreased in DEL-TnT compared with nontransgenic rats and TnT. Time parameters of Ca²⁺ transients were unchanged at 0.25 Hz but prolonged at 1.0 Hz in DEL-TnT. The amplitude of the fura-2 transient was similar in all groups investigated, whereas diastolic and systolic fura-2 ratios were found elevated in rats expressing nontruncated human troponin T. In DEL-TnT rats, myofibrillar Ca²⁺-dependent tension development as well as Ca²⁺ sensitivity of tension were significantly decreased, whereas tension-dependent ATP consumption ("tension cost") was markedly increased. Thus, a C-terminal truncation of the cardiac TnT molecule impairs the force-generating capacity of the cycling cross-bridges resulting in increased tension-dependent ATP utilization. Taken together, our data support the hypothesis of energy compromise as a contributing factor in the pathogenesis of FHC.

Received for publication, July 18, 2005 , and in revised form, July 5, 2006.

^* This work was supported in part by a grant from Köln Fortune (to K. B. and R. H. G. S.), Deutsche Forschungsgemeinschaft Grant Ka493/3-1 (to H. A. K., W. M. F., and N. F.), and SFB320 B/6 (to H. A. K. and W. M. F.). 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 a supplemental figure.

¹ Both authors contributed equally to this work.

² Supported by a Nationales Genomforschungsnetz grant from the German Ministry of Research and Education. To whom correspondence should be addressed: Dept. of Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel.: 49-6221-561505; Fax: 49-6221-564866; E-mail: Norbert_Frey{at}med.uni-heidelberg.de.

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