Myofibrillar Ca2+ sensitivity is uncoupled from troponin I phosphorylation in hypertrophic obstructive cardiomyopathy due to abnormal troponin T

Bayliss, Christopher R.; Jacques, Adam; Leung, Man-Ching; Ward, Douglas G.; Redwood, Charles; Gallon, Clare E.; Copeland, O'Neal; McKenna, William J.; Remedios, Cristobal dos; Marston, Steven B.; Messer, Andrew E.

doi:10.1093/cvr/cvs322

Cited by 31 publications

(51 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A case has been made that loss of this functional modulation of Ca 2+ -sensitivity through phosphorylation of TnI may play a pivotal role in HCM and DCM development and progression. The experiments using reconstituted thin filamnets in the in vitro motility assay provide a strong support that blunted response is one of the common abnormalities seen for both DCM [76,99,100] and HCM mutations [101,102]. It is interesting, that the effect was observed even if pathogenic mutations were not in thin filaments but in other sarcomeric proteins (myosin and MyBP-C) which were not present in the in vitro test system [76,101].…”

Section: Contractile Properties Of Hcm and Dcm Heartsmentioning

confidence: 90%

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Vikhorev

Vikhoreva

2018

IJMS

View full text Add to dashboard Cite

About half of hypertrophic and dilated cardiomyopathies cases have been recognized as genetic diseases with mutations in sarcomeric proteins. The sarcomeric proteins are involved in cardiomyocyte contractility and its regulation, and play a structural role. Mutations in non-sarcomeric proteins may induce changes in cell signaling pathways that modify contractile response of heart muscle. These facts strongly suggest that contractile dysfunction plays a central role in initiation and progression of cardiomyopathies. In fact, abnormalities in contractile mechanics of myofibrils have been discovered. However, it has not been revealed how these mutations increase risk for cardiomyopathy and cause the disease. Much research has been done and still much is being done to understand how the mechanism works. Here, we review the facts of cardiac myofilament contractility in patients with cardiomyopathy and heart failure.

show abstract

Section: Contractile Properties Of Hcm and Dcm Heartsmentioning

confidence: 90%

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Vikhorev

Vikhoreva

2018

IJMS

View full text Add to dashboard Cite

show abstract

“…In contrast, pathological samples from hearts transplanted for idiopathic dilated cardiomyopathy or septal myectomies from patients with hypertrophic obstructive cardiomyopathy (HOCM) generally have a low level of phosphorylation (0.1–0.4 mols Pi/mol TnI) (Van Der Velden et al, 2003; Messer et al, 2007, 2009; Zaremba et al, 2007; Ayaz-Guner et al, 2009; Hamdani et al, 2009; Jacques et al, 2009; Bayliss et al, 2012b). …”

Section: Methodsmentioning

confidence: 99%

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

Messer

Marston

2014

Front. Physiol.

Self Cite

View full text Add to dashboard Cite

Contraction in the mammalian heart is controlled by the intracellular Ca2+ concentration as it is in all striated muscle, but the heart has an additional signaling system that comes into play to increase heart rate and cardiac output during exercise or stress. β-adrenergic stimulation of heart muscle cells leads to release of cyclic-AMP and the activation of protein kinase A which phosphorylates key proteins in the sarcolemma, sarcoplasmic reticulum and contractile apparatus. Troponin I (TnI) and Myosin Binding Protein C (MyBP-C) are the prime targets in the myofilaments. TnI phosphorylation lowers myofibrillar Ca2+-sensitivity and increases the speed of Ca2+-dissociation and relaxation (lusitropic effect). Recent studies have shown that this relationship between Ca2+-sensitivity and TnI phosphorylation may be unstable. In familial cardiomyopathies, both dilated and hypertrophic (DCM and HCM), a mutation in one of the proteins of the thin filament often results in the loss of the relationship (uncoupling) and blunting of the lusitropic response. For familial dilated cardiomyopathy in thin filament proteins it has been proposed that this uncoupling is causative of the phenotype. Uncoupling has also been found in human heart tissue from patients with hypertrophic obstructive cardiomyopathy as a secondary effect. Recently, it has been found that Ca2+-sensitizing drugs can promote uncoupling, whilst one Ca2+-desensitizing drug Epigallocatechin 3-Gallate (EGCG) can reverse uncoupling. We will discuss recent findings about the role of uncoupling in the development of cardiomyopathies and the molecular mechanism of the process.

show abstract

“…29 Namely, the magnitude of the effects of PKA on the mechanical properties is less in diseased hearts. [47][48][49][50] Therefore, this uncoupling may be preserved in cTnI-K36Q myofibrils even after replacement of Tn, resulting in slowing of the kinetics of Ca-SPOC. We consider the mechanism of the uncoupling as follows: increased or decreased basal PKA-based phosphorylation levels of other sarcomere proteins (ie, MyBP-C and titin: see discussions below) within the sarcomere occur as compensatory responses because of the chronic history of the cTnI-K36Q mutation that is maintained even after pcTn reconstitution.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Myofibrillar Ca2+ sensitivity is uncoupled from troponin I phosphorylation in hypertrophic obstructive cardiomyopathy due to abnormal troponin T

Abstract: An abnormality in TnT is responsible for uncoupling myofibrillar Ca(2+) sensitivity from TnI phosphorylation in the septum of HOCM patients.

Cited by 31 publications

References 46 publications

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

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

Contact Info

Product

Resources

About