Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice

Alves, Marco L.; Warren, Chad M.; Simon, Jillian N.; Gaffin, Robert D.; Montminy, Eric M.; Wieczorek, David F.; Solaro, R. John; Wolska, Beata M.

doi:10.1093/cvr/cvx068

Cited by 22 publications

(17 citation statements)

References 56 publications

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“…In general, myofilament incorporation of troponin variants that cause opposing effects on thin filament Ca 2+ responsiveness are expected to normalize the myofilament Ca 2+ sensitivity Alves et al, 2014Alves et al, , 2017Dieseldorff Jones et al, 2018), and that was what was found in this study. Compared to WT, the 50%:50% mix of D132N/D145E showed similar myofilament Ca 2+ sensitivity and Hill coefficient (n Hill ) values, the latter generally reflecting cooperative processes associated with isometric force generation.…”

Section: Implications For Ctnc Function In the Cardiac Thin Filamentsupporting

confidence: 80%

Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

Landim-Vieira

Johnston

et al. 2020

Front. Physiol.

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Familial dilated cardiomyopathy (DCM), clinically characterized by enlargement and dysfunction of one or both ventricles of the heart, can be caused by variants in sarcomeric genes including TNNC1 (encoding cardiac troponin C, cTnC). Here, we report the case of two siblings with severe, early onset DCM who were found to have compound heterozygous variants in TNNC1: p.Asp145Glu (D145E) and p.Asp132Asn (D132N), which were inherited from the parents. We began our investigation with CRISPR/Cas9 knockout of TNNC1 in Xenopus tropicalis, which resulted in a cardiac phenotype in tadpoles consistent with DCM. Despite multiple maneuvers, we were unable to rescue the tadpole hearts with either human cTnC wild-type or patient variants to investigate the cardiomyopathy phenotype in vivo. We therefore utilized porcine permeabilized cardiac muscle preparations (CMPs) reconstituted with either wild-type or patient variant forms of cTnC to examine effects of the patient variants on contractile function. Incorporation of 50% WT/50% D145E into CMPs increased Ca 2+ sensitivity of isometric force, consistent with prior studies. In contrast, incorporation of 50% WT/50% D132N, which had not been previously reported, decreased Ca 2+ sensitivity of isometric force. CMPs reconstituted 50-50% with both variants mirrored WT in regard to myofilament Ca 2+ responsiveness. Sinusoidal stiffness (SS) (0.2% peak-to-peak) and the kinetics of tension redevelopment (k TR ) at saturating Ca 2+ were similar to WT for all preparations. Modeling of Ca 2+ -dependence of k TR support the observation from Ca 2+ responsiveness of steady-state isometric force, that the effects on each mutant (50% WT/50% mutant) were greater than the combination of the two mutants (50% D132N/50% D145E). Further studies are needed to ascertain the mechanism(s) of these variants.

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Section: Implications For Ctnc Function In the Cardiac Thin Filamentsupporting

confidence: 80%

Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

Landim-Vieira

Johnston

et al. 2020

Front. Physiol.

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“…Decreased myofilament Ca 2+ sensitivity has been identified as an important factor leading to DCM caused by thin-filament-associated mutations, and early sensitization of myofilaments to Ca 2+ may be used as a therapeutic target to treat thin-filament-linked DCM (Du et al. , 2007; Alves et al. , 2017).…”

Section: Discussionmentioning

confidence: 99%

Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics

Pappas

Johnson

et al. 2019

MBoC

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Missense mutations K15N and R21H in striated muscle tropomyosin are linked to dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Tropomyosin, together with the troponin complex, regulates muscle contraction and, along with tropomodulin and leiomodin, controls the uniform thin-filament lengths crucial for normal sarcomere structure and function. We used Förster resonance energy transfer to study effects of the tropomyosin mutations on the structure and kinetics of the cardiac troponin core domain associated with the Ca2+-dependent regulation of cardiac thin filaments. We found that the K15N mutation desensitizes thin filaments to Ca2+ and slows the kinetics of structural changes in troponin induced by Ca2+ dissociation from troponin, while the R21H mutation has almost no effect on these parameters. Expression of the K15N mutant in cardiomyocytes decreases leiomodin’s thin-filament pointed-end assembly but does not affect tropomodulin’s assembly at the pointed end. Our in vitro assays show that the R21H mutation causes a twofold decrease in tropomyosin’s affinity for F-actin and affects leiomodin’s function. We suggest that the K15N mutation causes DCM by altering Ca2+-dependent thin-filament regulation and that one of the possible HCM-causing mechanisms by the R21H mutation is through alteration of leiomodin’s function.

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“…Research has determined that there is a correlation between activation of the ERK1/2 pathway and HCM, whereas inhibition of the ERK pathway results in DCM [37]. Our previous investigations found that Tpm 54 DCM hearts have alterations in the levels of various kinases, including ERK1/2 and phosphor ERK1/2 [38]. In the Tpm S283D hearts, we find decreased expression of ERK1/2, phosphorylated ERK1/2, phosphorylated RSK3, and JNK1 which are members of the ERK pathway and associated with DCM.…”

Section: Constitutive Phosphorylation Of Tpm Leads To Dilated Cardiommentioning

confidence: 91%

The Role of Tropomyosin in Cardiac Function and Disease

Wieczorek¹

2019

Cardiac Diseases and Interventions in 21st Century

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Phosphorylation of cardiac sarcomeric proteins plays a major role in the regulation of physiological performance of the heart. Tropomyosin, an essential thin filament protein, regulates muscle contraction and relaxation through its interactions with actin, myosin, and the troponin complex. Studies demonstrate that changes in tropomyosin phosphorylation occur both postpartum and in response to cardiac hypertrophy and heart failure. To address the significance of tropomyosin phosphorylation on cardiac function, we conducted experiments to ascertain the effects of constitutive pseudophosphorylation, dephosphorylation, and dephosphorylation in hypertrophic cardiomyopathic hearts. Recent work demonstrates that pseudophosphorylation of tropomyosin results in dilated cardiomyopathy. Tropomyosin dephosphorylation results in a compensated or physiological cardiac hypertrophic phenotype. In addition, we demonstrated that tropomyosin dephosphorylation phenotypically rescues hearts undergoing cardiac hypertrophy. In summary, these studies collectively demonstrate a significant biological and physiological role for tropomyosin phosphorylation under both normal and cardiomyopathic conditions.

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Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice

Abstract: Our data indicate that decreased myofilament Ca2+ sensitivity is an essential element in the pathophysiology of thin filament linked DCM. Sensitization of myofilaments to Ca2+ in the early stage of DCM may be a useful therapeutic strategy in thin filament linked DCM.

Cited by 22 publications

References 56 publications

Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics

The Role of Tropomyosin in Cardiac Function and Disease

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