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J. Biol. Chem., Vol. 283, Issue 48, 33119-33128, November 28, 2008

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Challenging Current Paradigms Related to Cardiomyopathies

ARE CHANGES IN THE Ca²⁺ SENSITIVITY OF MYOFILAMENTS CONTAINING CARDIAC TROPONIN C MUTATIONS (G159D AND L29Q) GOOD PREDICTORS OF THE PHENOTYPIC OUTCOMES?^*

David Dweck, Nir Hus, and James D. Potter¹

From the Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136 and the Department of Surgery, Mount Sinai Medical Center, Miami Beach, Florida 33141

Two novel mutations (G159D and L29Q) in cardiac troponin C (CTnC) associate their phenotypic outcomes with dilated (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Current paradigms propose that sarcomeric mutations associated with DCM decrease the myofilament Ca²⁺ sensitivity, whereas those associated with HCM increase it. Therefore, we incorporated the mutant CTnCs into skinned cardiac muscle in order to determine if their effects on the Ca²⁺ sensitivities of tension and ATPase activity coincide with the current paradigms and phenotypic outcomes. The G159D-CTnC decreases the Ca²⁺ sensitivity of tension and ATPase activation and reduces the maximal ATPase activity when incorporated into regulated actomyosin filaments. Under the same conditions, the L29Q-CTnC has no effect. Surprisingly, changes in the apparent G159D-CTnC Ca²⁺ affinity measured by tension in fibers do not occur in the isolated CTnC, and large changes measured in the isolated L29Q-CTnC do not manifest in the fiber. These counterintuitive findings are justified through a transition in Ca²⁺ affinity occurring at the level of cardiac troponin and higher, implying that the true effects of these mutations become apparent as the hierarchical level of the myofilament increases. Therefore, the contractile apparatus, representing a large cooperative machine, can provide the potential for a change (G159D) or no change (L29Q) in the Ca²⁺ regulation of contraction. In accordance with the clinical outcomes and current paradigms, the desensitization of myofilaments from G159D-CTnC is expected to weaken the contractile force of the myocardium, whereas the lack of myofilament changes from L29Q-CTnC may preserve diastolic and systolic function.

Received for publication, May 28, 2008 , and in revised form, September 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL67415 and HL42325 (to J. D. P.) and T32-HL07188. This work was also supported by American Heart Association Grant AHA 0315164B (to D. D.). 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, Miller School of Medicine, 1600 NW 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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				J. R. Pinto, M. S. Parvatiyar, M. A. Jones, J. Liang, M. J. Ackerman, and J. D. Potter A Functional and Structural Study of Troponin C Mutations Related to Hypertrophic Cardiomyopathy J. Biol. Chem., July 10, 2009; 284(28): 19090 - 19100. [Abstract] [Full Text] [PDF]