Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 20, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm114
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Lys184 deletion in troponin I impairs relaxation kinetics and induces hypercontractility in murine cardiac myofibrils
1 Institute of Vegetative Physiology, University of Cologne, Cologne-50931, Germany
2 Center of Molecular Medicine of Cologne, Cologne-50931, Germany
3 Department of Physics and Applied Mathematics, Faculty of Chemistry, University of Bucharest, Bucharest-030018, Romania
Department where the work was performed: Institute of Vegetative Physiology, University of Cologne, Cologne-50931, Germany
Corresponding author: Bogdan Iorga Institute of Vegetative Physiology University of Cologne Robert-Koch-Strasse 39 Cologne-50931, Germany Tel: +49.221.478.6948 Fax: +49.221.478.3538 E-mail: bogdan.iorga{at}uni-koeln.de
Aim: To understand the functional consequences of the Lys184-deletion in murine cardiac troponin I (mcTnI(K184), we have studied the primary effects of this mutation linked to familial hypertrophic cardiomyopathy (FHC) at the sarcomeric level.
Methods: Ca2+ sensitivity and kinetics of force development and relaxation were investigated in cardiac myofibrils from transgenic mice expressing mcTnI(K184, as a model which co-segregates with FHC. Ca2+-dependent conformational changes (switch-on/off) of the fluorescence-labeled human troponin complex, containing either wild-type hcTnI or the mutant hcTnI(K183, were investigated in myofibrils prepared from the guinea pig left ventricle.
Results: 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, which traps cross-bridges in non-force-generating states.
Conclusions: We conclude that these changes are not due to the 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 mutation may underlie the enhanced systolic function and diastolic dysfunction at sarcomeric level.
KEYWORDS Ca2+ sensitization; cross-bridge kinetics; diastolic dysfunction; hypercontractility; sarcomere dynamics
Time for primary review: 19
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