title: Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice.
abstract: Familial hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere and may lead to hypertrophic, dilated, restrictive, and/or arrhythmogenic cardiomyopathy, congestive heart failure, or sudden cardiac death. We hypothesized that hearts from transgenic HCM mice harboring a mutant myosin heavy chain increase the energetic cost of contraction in a sex-specific manner. To do this, we assessed Ca(2+) sensitivity of tension and crossbridge kinetics in demembranated cardiac trabeculas from male and female wild-type (WT) and HCM hearts at an early time point (2 mo of age). We found a significant effect of sex on Ca(2+) sensitivity such that male, but not female, HCM mice displayed a decrease in Ca(2+) sensitivity compared with WT counterparts. The HCM transgene and sex significantly impacted the rate of force redevelopment by a rapid release-restretch protocol and tension cost by the ATPase-tension relationship. In each of these measures, HCM male trabeculas displayed a gain-of-function when compared with WT counterparts. In addition, cardiac remodeling measured by echocardiography, histology, morphometry, and posttranslational modifications demonstrated sex- and HCM-specific effects. In conclusion, female and male HCM mice display sex dimorphic crossbridge kinetics accompanied by sex- and HCM-dependent cardiac remodeling at the morphometric, histological, and cellular level.
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; Department of Biomedical Engineering, University of Arizona, Tucson, Arizona;
authors.forename: Camille L
authors.initials: CL
authors.lastname: Birch
authors.affiliation: Department of Physiology, University of Arizona, Tucson, Arizona; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona;
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Behunin
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; Department of Biomedical Engineering, University of Arizona, Tucson, Arizona;
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Lopez-Pier
authors.affiliation: Department of Physiology, University of Arizona, Tucson, Arizona; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona;
authors.forename: Christiane
authors.initials: C
authors.lastname: Danilo
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona; and.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Lipovka
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Chandra
authors.initials: C
authors.lastname: Saripalli
authors.affiliation: Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.affiliation: Department of Physiology, University of Arizona, Tucson, Arizona; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; konhilas@arizona.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Konhilas
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D012518:Sarcomeres / Q000201:enzymology*; D012727:Sex Characteristics; D012737:Sex Factors; D020257:Ventricular Remodeling
chemical_list: C551613:Myh7 protein, mouse; D000255:Adenosine Triphosphate; D018995:Myosin Heavy Chains
keywords: crossbridge cycle; sex/gender