HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free All Versions of this Article: fj.08-118182v1 fj.08-118182v2 23/3/855    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kerrick, W. G. L. Articles by Szczesna-Cordary, D. Search for Related Content PubMed PubMed Citation Articles by Kerrick, W. G. L. Articles by Szczesna-Cordary, D.

Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice

W. Glenn L. Kerrick^*, Katarzyna Kazmierczak, Yuanyuan Xu^*, Yingcai Wang and Danuta Szczesna-Cordary^,1

^* Department of Physiology and Biophysics and

Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida, USA

¹Correspondence: Dept. of Molecular and Cellular Pharmacology (R-189), University of Miami School of Medicine, P.O. Box 016189, 1600 NW 10th Avenue, Room 6113, Miami, FL 33101, USA. E-mail: dszczesna{at}med.miami.edu

Transgenic (Tg) mice expressing 95% of the D166V (aspartic acid to valine) mutation in the ventricular myosin regulatory light chain (RLC) shown to cause a malignant familial hypertrophic cardiomyopathy (FHC) phenotype were generated, and the skinned and intact papillary muscle fibers from the Tg-D166V mice were examined using a Guth muscle research system. A large increase in the Ca²⁺ sensitivity of force and ATPase (pCa₅₀>0.25) and a significant decrease in maximal force and ATPase were observed in skinned muscle fibers from Tg-D166V mice compared with control mice. The cross-bridge dissociation rate g was dramatically decreased, whereas the energy cost (ATPase/force) was slightly increased in Tg-D166V fibers compared with controls. The calculated average force per D166V cross-bridge was also reduced. Intact papillary muscle data demonstrated prolonged force transients with no change in calcium transients in Tg-D166V fibers compared with control fibers. Histopathological examination revealed fibrotic lesions in the hearts of the older D166V mice. Our results suggest that a charge effect of the D166V mutation and/or a mutation-dependent decrease in RLC phosphorylation could initiate the slower kinetics of the D166V cross-bridges and ultimately affect the regulation of cardiac muscle contraction. Profound cellular changes observed in Tg-D166V myocardium when placed in vivo could trigger a series of pathological responses and result in poor prognosis for D166V-positive patients.—Kerrick, W. G. L., Kazmierczak, K., Xu, Y., Wang, Y., Szczesna-Cordary, D. Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice.

Key Words: phosphorylation • calcium and force transients • cross-bridge dissociation rate • energy cost • ATPase-pCa dependence