Functional effects of DCM mutation G159D in troponin C from an explanted heart

Dyer, Ellie E.; Jacques, Adam; Burch, Milbre; Kaski, Juan Pablo; Marston, Steven B.

doi:10.1016/j.yjmcc.2008.02.045

Cited by 2 publications

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“…While these molecules may be useful for investigating the physiology of the sarcomere, they may produce misleading results in the context of identifying the disease mechanisms in HCM. Work with recombinant proteins other than myosin has also shown that the effect of a mutation is often very contextdependent, being influenced by isoform type, species of origin, and posttranslational modifications especially phosphorylation [5,13]. Investigations of the effects of admixture of mutant and wild-type proteins have shown the importance of studying 50:50 mixtures, as are expected in a heterozygous disease [49,52,51].…”

Section: Disparate Models Disparate Resultsmentioning

confidence: 99%

Mechanical and Energetic Consequences of HCM-Causing Mutations

Ferrantini

Belus

Piroddi

et al. 2009

J. of Cardiovasc. Trans. Res.

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Hypertrophic cardiomyopathy (HCM) was the first inherited heart disease to be characterized at the molecular genetic level with the demonstration that it is caused by mutations in genes that encode different components of the cardiac sarcomere. Early functional in vitro studies have concluded that HCM mutations cause a loss of sarcomere mechanical function. Hypertrophy would then follow as a compensatory mechanism to raise the work and power output of the affected heart. More recent in vitro and mouse model studies have suggested that HCM mutations enhance contractile function and myofilament Ca(2+) sensitivity and impair cardiac myocyte energetics. It has been hypothesized that these changes may result in cardiac myocyte energy depletion due to inefficient ATP utilization and also in altered myoplasmic Ca(2+) handling. The problems encountered in reaching a definitive answer on the effects of HCM mutations are discussed. Though direct analysis of the altered functional characteristics of HCM human cardiac sarcomeres has so far lagged behind the in vitro and mouse studies, recent work with mechanically isolated skinned myocytes and myofibrils from affected human hearts seem to support the energy depletion hypothesis. If further validated in the human heart, this hypothesis would identify tractable therapeutic targets that suggest that HCM, perhaps more than any other cardiomyopathy, will be amenable to disease-modifying therapy.

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Section: Disparate Models Disparate Resultsmentioning

confidence: 99%

Mechanical and Energetic Consequences of HCM-Causing Mutations

Ferrantini

Belus

Piroddi

et al. 2009

J. of Cardiovasc. Trans. Res.

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“…This trait, which we have termed “uncoupling,” was first noted in 2001 ( 27 , 28 ). In 2007-8 three publications studying the recently discovered TNNC1 G159D mutation showed uncoupling with recombinant mutant troponin, with troponin extracted from a patient with the mutation and with rat trabecula with the mutation exchanged in myocytes ( 29 – 31 ). Subsequently, almost every thin filament mutation that was tested proved to be uncoupled.…”

Section: Mutations Can Also Suppress Lusitropymentioning

confidence: 99%

Suppression of lusitropy as a disease mechanism in cardiomyopathies

Marston

Pinto

2023

Front. Cardiovasc. Med.

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In cardiac muscle the action of adrenaline on β1 receptors of heart muscle cells is essential to adjust cardiac output to the body’s needs. Adrenergic activation leads to enhanced contractility (inotropy), faster heart rate (chronotropy) and faster relaxation (lusitropy), mainly through activation of protein kinase A (PKA). Efficient enhancement of heart output under stress requires all of these responses to work together. Lusitropy is essential for shortening the heartbeat when heart rate increases. It therefore follows that, if the lusitropic response is not present, heart function under stress will be compromised. Current literature suggests that lusitropy is primarily achieved due to PKA phosphorylation of troponin I (TnI) and phospholamban (PLB). It has been well documented that PKA-induced phosphorylation of TnI releases Ca2+ from troponin C faster and increases the rate of cardiac muscle relaxation, while phosphorylation of PLB increases SERCA activity, speeding up Ca2+ removal from the cytoplasm. In this review we consider the current scientific evidences for the connection between suppression of lusitropy and cardiac dysfunction in the context of mutations in phospholamban and thin filament proteins that are associated with cardiomyopathies. We will discuss what advances have been made into understanding the physiological mechanism of lusitropy due to TnI and PLB phosphorylation and its suppression by mutations and we will evaluate the evidence whether lack of lusitropy is sufficient to cause cardiomyopathy, and under what circumstances, and consider the range of pathologies associated with loss of lusitropy. Finally, we will discuss whether suppressed lusitropy due to mutations in thin filament proteins can be therapeutically restored.

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Functional effects of DCM mutation G159D in troponin C from an explanted heart

Cited by 2 publications

References 0 publications

Mechanical and Energetic Consequences of HCM-Causing Mutations

Mechanical and Energetic Consequences of HCM-Causing Mutations

Suppression of lusitropy as a disease mechanism in cardiomyopathies

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