title: 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.
abstract: Transgenic (Tg) mice expressing approximately 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 Ca(2+) sensitivity of force and ATPase (Delta pCa(50)>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.
authors.affiliation: Dept. of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: W Glenn L
authors.initials: WG
authors.lastname: Kerrick
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kazmierczak
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.forename: Danuta
authors.initials: D
authors.lastname: Szczesna-Cordary
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics* / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D010210:Papillary Muscles / Q000502:physiology*; D010766:Phosphorylation; D011487:Protein Conformation
chemical_list: D018994:Myosin Light Chains; D000251:Adenosine Triphosphatases; D009218:Myosins; D002118:Calcium