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J. Biol. Chem., Vol. 283, Issue 22, 15114-15121, May 30, 2008

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Increased Cross-bridge Cycling Kinetics after Exchange of C-terminal Truncated Troponin I in Skinned Rat Cardiac Muscle^*

From the Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois 60612

The precise mechanism of cardiac troponin I (cTnI) proteolysis in myocardial stunning is not fully understood. Accordingly, we determined the effect of cTnI C terminus truncation on chemo-mechanical transduction in isolated skinned rat trabeculae. Recombinant troponin complex (cTn), containing either mouse cTnI-(1–193) or human cTnI-(1–192) was exchanged into skinned cardiac trabeculae; Western blot analysis confirmed that 60–70% of the endogenous cTn was replaced by recombinant Tn. Incorporation of truncated cTnI induced significant reductions (50%) in maximum force and cooperative activation as well as increases (50%) in myofilament Ca²⁺ sensitivity and tension cost. Similar results were obtained with either mouse or human truncated cTn. Presence of truncated cTnI increased maximum actin-activated S1 ATPase activity as well as its Ca²⁺ sensitivity in vitro. Partial exchange (50%) for truncated cTnI resulted in similar reductions in maximum force and cooperativity; tension cost was increased in proportion to truncated cTnI content. In vitro, to determine the molecular mechanism responsible for the enhanced myofilament Ca²⁺ sensitivity, we measured Ca²⁺ binding to cTn as reported using a fluorescent probe. Incorporation of truncated cTnI did not affect Ca²⁺ binding affinity to cTn alone. However, when cTn was incorporated into thin filaments, cTnI truncation induced a significant increase in Ca²⁺ binding affinity to cTn. We conclude that cTnI truncation induces depressed myofilament function. Decreased cardiac function after ischemia/reperfusion injury may directly result, in part, from proteolytic degradation of cTnI, resulting in alterations in cross-bridge cycling kinetics.

Received for publication, February 28, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL62426, HL77195, HL75494, HL082923, HL22231, HL07692, and HL072742. This study was supported in part by American Heart Association Predoctoral Fellowship 0615597Z (to K. T.). 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: 835 S. Wolcott, Physiology and Biophysics MC901, Chicago, IL 60612. Tel.: 312-355-0259; Fax: 312-355-0261; E-mail: pdetombe{at}uic.edu.

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				T. Kobayashi, S. E. Patrick, and M. Kobayashi Ala Scanning of the Inhibitory Region of Cardiac Troponin I J. Biol. Chem., July 24, 2009; 284(30): 20052 - 20060. [Abstract] [Full Text] [PDF]