Key result
Male but not female transgenic HCM mice show decreased calcium sensitivity and enhanced crossbridge kinetics.
Male and female HCM mice display sex-dimorphic crossbridge kinetics and cardiac remodeling, suggesting sex-specific pathophysiological mechanisms in early hypertrophic cardiomyopathy.
Sex-specific sarcomere kinetics in HCM mice highlight modeling bias; leaves open human translation and clinical relevance.
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.
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Birch et al. (2016) studied Familial hypertrophic cardiomyopathy (HCM). Mutant myosin heavy chain (HCM transgene) vs. Wild-type (WT) was evaluated on Ca(2+) sensitivity of tension and crossbridge kinetics. Male, but not female, transgenic HCM mice displayed a decrease in Ca(2+) sensitivity and a gain-of-function in crossbridge kinetics compared with wild-type counterparts.
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