Pathogenesis of depression‐ and anxiety‐like behavior in an animal model of hypertrophic cardiomyopathy

Dossat, Amanda M.; Sanchez-Gonzalez, Marcos A.; Koutnik, Andrew P.; Leitner, Stefano; Ruiz, Edda L.; Griffin, Brittany; Rosenberg, Jens T.; Grant, Samuel C.; Fincham, Frank D.; Pinto, José R.; Kabbaj, Mohamed

doi:10.1096/fj.201600955rr

Cited by 8 publications

(7 citation statements)

References 108 publications

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“…Cardiac ultrasound of HCM mice revealed hemodynamic and physical dimensions similar to previously reported values (Dossat et al, 2017; Martins et al, 2015) (see Figure 1 and its corresponding Table 1). For example, the HCM mice exhibited a similar disease phenotype with overall thicker left ventricular walls and a smaller chamber size than WT mice, as compared to previous work (see Figure 1a and Table 1).…”

Section: Resultssupporting

confidence: 87%

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Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

et al. 2020

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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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Section: Resultssupporting

confidence: 87%

“…Cardiac ultrasound of HCM mice revealed hemodynamic and physical dimensions similar to previously reported values(Dossat et al, 2017;Martins et al, 2015) (seeFigure 1and its corresponding…”

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confidence: 86%

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

et al. 2020

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“…M-mode imaging of the parasternal short axis view allowed evaluation of left ventricular systolic and diastolic function and morphology. The mitral valve flow parameters were acquired through a four-chamber view using the pulsed wave spectral Doppler to be used as an index of diastolic function [21, 22]. …”

Section: Methodsmentioning

confidence: 99%

Pathogenic troponin T mutants with opposing effects on myofilament Ca2+ sensitivity attenuate cardiomyopathy phenotypes in mice

Jones

Koh

Weller

et al. 2019

Archives of Biochemistry and Biophysics

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Mutations in cardiac troponin T (TnT) associated with hypertrophic cardiomyopathy generally lead to an increase in the Ca2+ sensitivity of contraction and susceptibility to arrhythmias. In contrast, TnT mutations linked to dilated cardiomyopathy decrease the Ca2+ sensitivity of contraction. Here we tested the hypothesis that two TnT disease mutations with opposite effects on myofilament Ca2+ sensitivity can attenuate each other’s phenotype. We crossed transgenic mice expressing the HCM TnT-I79N mutation (I79N) with a DCM knock-in mouse model carrying the heterozygous TnT-R141W mutation (HET). The results of the Ca2+ sensitivity in skinned cardiac muscle preparations ranked from highest to lowest were as follow: I79N > I79N/HET > NTg > HET. Echocardiographic measurements revealed an improvement in hemodynamic parameters in I79N/HET compared to I79N and normalization of left ventricular dimensions and volumes compared to both I79N and HET. Ex vivo testing showed that the I79N/HET mouse hearts had reduced arrhythmia susceptibility compared to I79N mice. These results suggest that two disease mutations in TnT that have opposite effects on the myofilament Ca2+ sensitivity can paradoxically ameliorate each other’s disease phenotype. Normalizing myofilament Ca2+ sensitivity may be a promising new treatment approach for a variety of diseases.

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“…These mice have been previously characterized and published by our group (20, 21). KI-TnC-A8V +/+ mice were shown to develop HCM in the adult stage (20, 22) and are therefore denoted as “HCM.” All animals used in this study ranged from 7–10 months of age.…”

Section: Methodsmentioning

confidence: 99%

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Gonzalez-Martinez

Johnston

Landim-Vieira

et al. 2018

Journal of Molecular and Cellular Cardiology

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Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca sensitizer. Our findings suggest that both methods of increasing myofilament Ca sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (k); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I/I ratio from X-ray diffraction. Computational modeling suggests that Ca sensitization through this cTnC mutation or bepridil accelerates k primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in k, we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.

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Pathogenesis of depression‐ and anxiety‐like behavior in an animal model of hypertrophic cardiomyopathy

Cited by 8 publications

References 108 publications

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

Pathogenic troponin T mutants with opposing effects on myofilament Ca2+ sensitivity attenuate cardiomyopathy phenotypes in mice

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

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