Independent FHC-related cardiac troponin T mutations exhibit specific alterations in myocellular contractility and calcium kinetics

Haïm, T; Dowell, Candice; Diamanti, Theodhor; Scheuer, James; Tardiff, Jil C.

doi:10.1016/j.yjmcc.2007.03.906

Cited by 47 publications

(59 citation statements)

References 46 publications

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“…This provides a plausible hypothesis to explain arrhythmias and sudden cardiac death in HCM. It is notable that the risk of sudden cardiac death is higher with certain mutations and correlates with the degree of increased Ca 2+ -sensitivity measured in vitro [42]. On the other hand, the risk does not correlate with the degree of hypertrophy, suggesting a different pathway for this aspect of the HCM phenotype.…”

Section: How Can the Molecular Phenotype Cause The Disease Hcm?mentioning

confidence: 90%

How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?

Marston

2011

J. of Cardiovasc. Trans. Res.

114

131

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In this article, the available evidence about the functional effects of the contractile protein mutations that cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) is assessed. The molecular mechanism of the contractile apparatus of cardiac muscle and its regulation by Ca(2+) and PKA phosphorylation have been extensively studied. Therefore, when a number of point mutations in the contractile protein genes were found to cause the well-defined phenotypes of HCM and DCM, it was expected that the diseases could be explained at the molecular level. However, the search for a distinctive molecular phenotype did not yield rapid results. Now that a substantial number of mutations that cause HCM or DCM have been investigated in physiologically relevant systems and with a range of experimental techniques, a pattern is emerging. In the case of HCM, the hypothesis that the major effect of mutations is to increase myofibrillar Ca(2+)-sensitivity seems to be well established, but the mechanisms by which an increase in myofibrillar Ca(2+)-sensitivity induces hypertrophy remain obscure. In contrast, DCM mutations are not correlated with a specific effect on Ca(2+)-sensitivity. It has recently been proposed that DCM mutations uncouple troponin I phosphorylation from Ca(2+)-sensitivity changes, albeit based on only a few mutations so far. A plausible link between uncoupling and DCM has been proposed via blunting of the response to α-adrenergic stimulation.

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Section: How Can the Molecular Phenotype Cause The Disease Hcm?mentioning

confidence: 90%

How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?

Marston

2011

J. of Cardiovasc. Trans. Res.

114

131

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“…28 This mutation was first reported by Carballo et al, 28 who provided evidence that myofibrillar ATPase and thin filament Ca 2+ affinity were both reduced in the proband. Therefore, yet it is widely accepted that constant changes in the dynamic properties of the beating heart, that is, the kinetics of Ca 2+ transients or that of force generation, rather than steady-state Ca 2+ sensitivity, underlie the pathogenesis of DCM, 46 we consider that the chronic presence of the cTnI-K36Q mutation is the only confounding factor that causes DCM.…”

Section: Discussionmentioning

confidence: 99%

Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy

Kagemoto

Oyama

Yamane

et al. 2018

Circ: Heart Failure

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Background: Left ventricular wall motion is depressed in patients with dilated cardiomyopathy (DCM). However, whether or not the depressed left ventricular wall motion is caused by impairment of sarcomere dynamics remains to be fully clarified. Methods and Results: We analyzed the mechanical properties of single sarcomere dynamics during sarcomeric auto-oscillations (calcium spontaneous oscillatory contractions [Ca-SPOC]) that occurred at partial activation under the isometric condition in myofibrils from donor hearts and from patients with severe DCM (New York Heart Association classification III-IV). Ca-SPOC reproducibly occurred in the presence of 1 μmol/L free Ca 2+ in both nonfailing and DCM myofibrils, and sarcomeres exhibited a saw-tooth waveform along single myofibrils composed of quick lengthening and slow shortening. The period of Ca-SPOC was longer in DCM myofibrils than in nonfailing myofibrils, in association with prolonged shortening time. Lengthening time was similar in both groups. Then, we performed Tn (troponin) exchange in myofibrils with a DCM-causing homozygous mutation (K36Q) in cTnI (cardiac TnI). On exchange with the Tn complex from healthy porcine ventricles, period, shortening time, and shortening velocity in cTnI-K36Q myofibrils became similar to those in Tn-reconstituted nonfailing myofibrils. Protein kinase A abbreviated period in both Tn-reconstituted nonfailing and cTnI-K36Q myofibrils, demonstrating acceleration of cross-bridge kinetics. Conclusions: Sarcomere dynamics was found to be depressed under loaded conditions in DCM myofibrils because of impairment of thick-thin filament sliding. Thus, microscopic analysis of Ca-SPOC in human cardiac myofibrils is beneficial to systematically unveil the kinetic properties of single sarcomeres in various types of heart disease.

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“…27 Alterations in Ca 2+ handling and kinetics in response to the expression of mutant sarcomeric proteins have been previously reported to be mutation specific. 28,29 A mutant mouse model of HCM carrying the R403Q α major histocompatibility complex shows a higher peak of Ca 2+ transients during twitch contraction without a change in force development. 29 A high number of Ca 2+ transients Fig.…”

Section: Discussionmentioning

confidence: 99%

Impairment of Ubiquitin–Proteasome System by E334K cMyBPC Modifies Channel Proteins, Leading to Electrophysiological Dysfunction

Bahrudin

Morikawa

Takeuchi

et al. 2011

Journal of Molecular Biology

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Independent FHC-related cardiac troponin T mutations exhibit specific alterations in myocellular contractility and calcium kinetics

Cited by 47 publications

References 46 publications

How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?

How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?

Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy

Impairment of Ubiquitin–Proteasome System by E334K cMyBPC Modifies Channel Proteins, Leading to Electrophysiological Dysfunction

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