In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 is a Hypertrophic Cardiomyopathy Susceptibility Gene

Martins, Adriano S.; Parvatiyar, Michelle S.; Turna, R.F.; Badger, Crystal Dawn; Griffin, Brittany; Zorio, Diego A. R.; Vukmirovic, Milica; Sanchez-Gonzalez, Marcos A.; Dweck, David; Ruiz, Edda L.; Liang, Jingsheng; Wang, Yincai; Overton, J. M.; Pinto, José R.

doi:10.1016/j.bpj.2013.11.3995

Cited by 12 publications

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“…Knock‐in homozygous mice bearing the mutation Ala8Val in cTnC, KI‐TnC‐A8V +/+ (HCM), and wild‐type (control) mice were generated as has been described (9). In brief, embryonic stem cells were electroporated with 25 μg of linearized DNA harboring the A8V mutation.…”

Section: Methodsmentioning

confidence: 99%

“…Two age groups were examined: young adult (age, 3.9 ± 0.6 mo, n = 8/group) and aged adults (7.2 ± 1.8 mo, n = 13–16/group). Because heterozygous males do not exhibit evidence of HCM until 14 mo of age (9), we used homozygous mice to investigate the impact of HCM in young adult and aged adult females, in the absence of other aging‐related health declines. Another group of aged adult control and HCM females were used for MRI volumetric analyses (age, 8.4 ± 0.2 mo, n = 4/group).…”

Section: Methodsmentioning

confidence: 99%

“…Sarcomeric mutations in cardiac troponin T, I, and C (cTnT, cTnI, and cTnC, respectively) have been documented in humans with an HCM phenotype (7, 8). Recently, we generated a knock‐in mouse bearing an HCM mutation in TNNC1 (gene encoding cTnC), which is expressed in the heart and slow skeletal muscles (9). Since its identification <10 yr ago (10), there have been additional reports of humans with the Ala8Val mutation in the TNNC1 gene, as well as phenotypic symptoms associated with HCM and restricted cardiomyopathy (RCM) (9, 11, 12).…”

mentioning

confidence: 99%

“…Recently, we generated a knock‐in mouse bearing an HCM mutation in TNNC1 (gene encoding cTnC), which is expressed in the heart and slow skeletal muscles (9). Since its identification <10 yr ago (10), there have been additional reports of humans with the Ala8Val mutation in the TNNC1 gene, as well as phenotypic symptoms associated with HCM and restricted cardiomyopathy (RCM) (9, 11, 12). As has been shown for other HCM troponin‐related mutations, the cTnCAla8Val mutation in the murine heart induces cardiac interstitial fibrosis, myofibrillar disarray, left atrial enlargement, diastolic dysfunction, and an increased ejection fraction (EF) (9, 13–16).…”

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confidence: 99%

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

et al. 2017

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Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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

et al. 2017

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“…Within the last 10 years, TNNC1 has been characterized as an HCM–susceptibility gene and mutations found in probands with a clinical diagnosis of cardiomyopathy (Landstrom et al, 2008). The encoded mutant cTnC proteins have been studied for their pathogenic effects in vitro and in vivo (Landstrom et al, 2008; Martins et al, 2015). The A8V variant of cTnC, caused by a point mutation in TNNC1 , markedly increases myofilament Ca 2+ sensitivity and kinetics of actomyosin cross‐bridge cycling (Gonzalez‐Martinez et al, 2018; Pinto et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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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Myosin Rod Hypophosphorylation and CB Kinetics in Papillary Muscles from a TnC-A8V KI Mouse Model

Kawai

Johnston

Karam

et al. 2017

Biophysical Journal

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The cardiac troponin C (TnC)-A8V mutation is associated with hypertrophic and restrictive cardiomyopathy (HCM and RCM) in human and mice. The residue affected lies in the N-helix, a region known to affect Ca-binding affinity to the N-terminal domain. Here we report on the functional effects of this mutation in skinned papillary muscle fibers from homozygous knock-in TnC-A8V mice. Muscle fibers from left ventricle were activated at 25°C under the ionic conditions of working cardiomyocytes. The pCa-tension relationship showed a 3× increase in Ca-sensitivity and a decrease (0.8×) in cooperativity (n) in mutant fibers. The elementary steps of the cross-bridge (CB) cycle were investigated by sinusoidal analysis. The ATP study revealed that there is no significant change in the affinity of ATP (K) for the myosin head. In TnC-A8V mutant fibers, the CB detachment rate (k) and its equilibrium constant (K) increased (1.5×). The phosphate study revealed that rate constant of the force-generation step (k) decreased (0.5×), reversal step (k) increased (2×), and the phosphate-release step (1/K) increased (2×). Pro-Q Diamond staining of the skinned fibers samples revealed no significant changes in total phosphorylation of multiple sarcomeric proteins. Further investigation using liquid chromatography-tandem mass spectrometry revealed hypophosphorylation of the rod domain of myosin heavy chain in TnC-A8V mutant fibers compared to wild-type. Immunoblotting confirmed the results observed in the mass spectrometry analysis. The results suggest perturbed CB kinetics-possibly caused by changes in the α-myosin heavy chain phosphorylation profile-as a novel mechanism, to our knowledge, by which a mutation in TnC can have rippling effects in the myofilament and contribute to the pathogenesis of HCM/RCM.

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In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 is a Hypertrophic Cardiomyopathy Susceptibility Gene

Cited by 12 publications

References 0 publications

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

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

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

Myosin Rod Hypophosphorylation and CB Kinetics in Papillary Muscles from a TnC-A8V KI Mouse Model

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