Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice

Author:

Birch Camille L.12,Behunin Samantha M.31,Lopez-Pier Marissa A.12,Danilo Christiane31,Lipovka Yulia14,Saripalli Chandra15,Granzier Henk15,Konhilas John P.31

Affiliation:

1. Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona;

2. Department of Biomedical Engineering, University of Arizona, Tucson, Arizona;

3. Department of Physiology, University of Arizona, Tucson, Arizona;

4. Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona; and

5. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona

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 Ca2+ 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 Ca2+ sensitivity such that male, but not female, HCM mice displayed a decrease in Ca2+ 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.

Funder

National Institutes of Health

National Mentored Research Science and Development

Interdisciplinary Training in Cardiovascular Research

Cardiovascular Biomedical Engineering Training Grant

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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