Key result
Female mice with the HCM-associated cTnC-A8V mutation exhibited a more severe decline in cardiac function and stronger alterations in key transcriptomic pathways compared to male mice.
Why the study?
Studies in female models remain underrepresented in cardiac research, and the transcriptomic basis underlying sexual dimorphism in HCM cardiac physiology was unknown.
Does the cTnC-A8V point mutation cause sexually dimorphic transcriptomic and physiological changes in a murine model of hypertrophic cardiomyopathy?
Does the cTnC-A8V point mutation cause sexually dimorphic transcriptomic and physiological changes in a murine model of hypertrophic cardiomyopathy?
A murine model of hypertrophic cardiomyopathy with a cTnC-A8V mutation exhibits sexually dimorphic cardiac physiology and transcriptomic profiles, highlighting potential targetable pathways for female-specific cardiac dysfunction.
Preclinical sex differences in this HCM model warrant caution in extrapolation; leaves open targeted human studies on female-specific pathways.
Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in both sexes. Among the susceptible genes, TNNC1-encoding cardiac troponin C (cTnC)-causes a substantial HCM phenotype in mice. Mice bearing an HCM-associated cTnC-A8V point mutation exhibited a significant decrease in stroke volume and left ventricular diameter and volume. Importantly, isovolumetric contraction time was significantly higher for female HCM mice. We utilized a transcriptomic approach to investigate the basis underlying the sexual dimorphism observed in the cardiac physiology of adult male and female HCM mice. RNA sequencing revealed several altered canonical pathways within the HCM mice versus WT groups including an increase in eukaryotic initiation factor 2 signaling, integrin-linked kinase signaling, actin nucleation by actin-related protein-Wiskott-Aldrich syndrome family protein complex, regulation of actin-based motility by Rho kinase, vitamin D receptor/retinoid X receptor activation, and glutathione redox reaction pathways. In contrast, valine degradation, tricarboxylic acid cycle II, methionine degradation, and inositol phosphate compound pathways were notably down-regulated in HCM mice. These down-regulated pathways may be reduced in response to altered energetics in the hypertrophied hearts and may represent conservation of energy as the heart is compensating to meet increased contractile demands. HCM male versus female mice followed similar trends of the canonical pathways altered between HCM and WT. In addition, seven of the differentially expressed genes in both WT and HCM male versus female comparisons swapped directions in fold-change between the sexes. These findings suggest a sexually-dimorphic HCM phenotype due to a sarcomeric mutation and pinpoint several key targetable pathways and genes that may provide the means to alleviate the more severe decline in female cardiac function.
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Jones et al. (2020) studied Hypertrophic cardiomyopathy (n=56). cTnC-A8V mutation vs. Wild-type was evaluated on Differentially expressed genes (RNA-seq) and echocardiographic parameters. Female mice with the HCM-associated cTnC-A8V mutation exhibited a more severe decline in cardiac function and stronger alterations in key transcriptomic pathways compared to male mice.
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