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Cardiovascular Research Advance Access first published online on December 20, 2007
This version [Corrected Proof] published online on January 25, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm113
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org.

Lys184 deletion in troponin I impairs relaxation kinetics and induces hypercontractility in murine cardiac myofibrils

Bogdan Iorga1,2,*, Natascha Blaudeck1, Johannes Solzin1,3, Axel Neulen1, Ina Stehle1, Alfredo J. Lopez Davila1, Gabriele Pfitzer1,3 and Robert Stehle1,3

1 Institute of Vegetative Physiology, University of Cologne, Robert-Koch-Strasse 39, Cologne 50931, Germany
2 Department of Physics and Applied Mathematics, Faculty of Chemistry, University of Bucharest, Bucharest 030018, Romania
3 Center for Molecular Medicine of Cologne, Cologne 50931, Germany

* Corresponding author. Tel: +49 221 478 6948; fax: +49 221 478 3538. E-mail address: bogdan.iorga{at}uni-koeln.de; robert.stehle{at}uni-koeln.de

Aims: To understand the functional consequences of the Lys184 deletion in murine cardiac troponin I (mcTnI{Delta}K184), we have studied the primary effects of this mutation linked to familial hypertrophic cardiomyopathy (FHC) at the sarcomeric level.

Methods and results: Ca2+ sensitivity and kinetics of force development and relaxation were investigated in cardiac myofibrils from transgenic mice expressing mcTnI{Delta}K184, as a model which co-segregates with FHC. Ca2+-dependent conformational changes (switch-on/off) of the fluorescence-labelled human troponin complex, containing either wild-type hcTnI or mutant hcTnI{Delta}K183, were investigated in myofibrils prepared from the guinea pig left ventricle. Ca2+ sensitivity and maximum Ca2+-activated and passive forces were significantly enhanced and cooperativity was reduced in mutant myofibrils. At partial Ca2+ activation, mutant but not wild-type myofibrils displayed spontaneous oscillatory contraction of sarcomeres. Both conformational switch-off rates of the incorporated troponin complex and the myofibrillar relaxation kinetics were slowed down by the mutation. Impaired relaxation kinetics and increased force at low [Ca2+] were reversed by 2,3-butanedione monoxime (BDM), which traps cross-bridges in non-force-generating states.

Conclusion: We conclude that these changes are not due to alterations of the intrinsic cross-bridge kinetics. The molecular mechanism of sarcomeric diastolic dysfunction in this FHC model is based on the impaired regulatory switch-off kinetics of cTnI, which induces incomplete inhibition of force-generating cross-bridges at low [Ca2+] and thereby slows down relaxation of sarcomeres. Ca2+ sensitization and impairment of the relaxation of sarcomeres induced by this mutation may underlie the enhanced systolic function and diastolic dysfunction at the sarcomeric level.

KEYWORDS Ca2+ sensitization; Cross-bridge kinetics; Diastolic dysfunction; Hypercontractility; Sarcomere dynamics

Time for primary review: 22 days


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