Skip Navigation


Cardiovascular Research Advance Access originally published online on December 20, 2007
Cardiovascular Research 2008 77(4):676-686; doi:10.1093/cvr/cvm113
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
77/4/676    most recent
cvm113v3
cvm113v2
cvm113v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Iorga, B.
Right arrow Articles by Stehle, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iorga, B.
Right arrow Articles by Stehle, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
R. J. Solaro and P. P. de Tombe
Review focus series: sarcomeric proteins as key elements in integrated control of cardiac function
Cardiovasc Res, March 1, 2008; 77(4): 616 - 618.
[Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.