The effect of myosin light chain 2 dephosphorylation on Ca-sensitivity of force is enhanced in failing human hearts

Velden, Jolanda van der; Papp, Zoltán; Boontje, Nicky M.; Zaremba, R.; Jong, Jan Willem de; Janssen, Paul M. L.; Hasenfuß, Gerd; Stienen, G. J. M.

doi:10.1016/s0008-6363(02)00662-4

Cited by 126 publications

(124 citation statements)

References 34 publications

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“…23 However, we did not observe a difference in myosin light chain 1 and troponin T phosphorylation between donor and failing hearts. 7,13 In this study, our primary aim was to explore the molecular background of the altered cardiac pump function during end-stage human heart failure. To obtain a more detailed picture, the determination of Ca 2+ -force relation was paralleled by k tr measurements in the absence or presence of ischaemic metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…myosin binding protein C, myosin light chain 2) have been consistently documented for progressed stages of human heart failure in association with ischaemic and/or dilated cardiomyopathy. 7,13,14 The Ca 2+ sensitivity of force production is a result of the cooperative interplay between the thin and thick filaments in striated muscles. 15,16 Thus, it is controlled not only by the Ca 2+ regulation of the thin filaments 17 but also by the kinetic properties of the actin-myosin cross-bridge cycle.…”

Section: Introductionmentioning

confidence: 99%

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Altered myocardial force generation in end‐stage human heart failure

et al. 2014

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Aims This study aimed to elucidate the molecular background of increased Ca 2+ sensitivity of force production in cardiomyocytes of end-stage human heart failure.Methods and results Ca 2+ -activated isometric force and the cross-bridge specific rate of force redevelopment (k tr ) were determined in Triton-skinned myocytes from end-stage failing and non-failing donor hearts. Measurements (control: pH 7.2, 0 mM inorganic phosphate (P i )) were performed under test conditions that probed either the Ca 2+ -regulatory function of the thin filaments (pH 6.5), the kinetics of the actin-myosin cross-bridge cycle (10 mM P i ), or both (pH 6.5, 10 mM P i ). The control maximal Ca 2+ -activated force (F o ) and k trmax did not differ between failing and non-failing myocytes. At submaximal [Ca 2+ ], however, both force and k tr were higher in failing than in donor myocytes. The difference in the Ca 2+ sensitivities of force production was preserved when the thin filament regulatory function was perturbed by acidosis (pH 6.5) but was abolished by cross-bridge modulation (i.e. by P i ) both at pH 7.2 and at pH 6.5. P i induced a larger reduction in force but a smaller increase in k tr in the failing myocytes than in the non-failing myocytes at submaximal [Ca 2+ ]. ConclusionThe enhanced P i sensitivity of the actin-myosin interaction suggests that the P i release step of the actin-myosin cross-bridge cycle is modified during end-stage human heart failure. This might be of functional importance when P i accumulates (e.g. during cardiac ischaemia). Moreover, this alteration can influence cardiac energetics and the clinical efficacy of sarcomere targeted agents in human heart failure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Altered myocardial force generation in end‐stage human heart failure

et al. 2014

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“…However, the phosphorylation level of MLC 2 was found to be decreased in the left ventricles of failing hearts (108,147), and the contractile response to MLC 2 dephosphorylation was enhanced (108). The latter observation was explained by a difference in the basal phosphorylation of thin and thick filament proteins.…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 93%

“…Recent results suggest that the difference in Ca 2+ responsiveness in the failing heart does not reflect intrinsic differences in the protein isoform composition, but rather represents a change in the endogenous phosphorylation status of thin and thick filament proteins (91,108,109). Such an alteration may be determined by the presence of different amounts of kinases, such as the cyclic AMP-dependent protein kinase A (PKA), protein kinase C (PKC) and myosin light chain kinase (MLCK), as well as phosphatases, in the failing myocardium.…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

“…The activation of the Rho-Rho kinase pathway was considered to induce the phosphorylation of MLC 2 , which leads to increased Ca 2+ sensitivity. However, the functional role of this pathway is questionable because MLC 2 phosphorylation was found to be decreased in HF (108,147). Despite conflicting results, the cardioprotective effect of specific Rho-kinase inhibitors on cardiac performance and cardiac remodelling (148) draws attention to a potential regulatory role of Rho kinases in heart function.…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

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Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Macháčková¹,

Barta²,

Dhalla³

2006

Canadian Journal of Cardiology

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Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy

et al. 2019

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Aims Cardiac myosin light chain kinase (cMLCK) phosphorylates ventricular myosin regulatory light chain 2 (MLC2v) and regulates sarcomere and cardiomyocyte organization. However, few data exist regarding the relationship between cMLCK mutations and MLC2v phosphorylation, particularly in terms of developing familial dilated cardiomyopathy (DCM) in whom cMLCK gene mutations were identified. The purpose of the present study was to investigate functional consequences of cMLCK mutations in DCM patients. Methods and results The diagnosis of DCM was based on the patients' history and on echocardiography. We screened cMLCK gene mutations in DCM probands with high resolution melting analysis. Known DCM‐causing genes mutations were excluded by exome sequencing of family members. MLC2v phosphorylation was analysed by Phos‐tag sodium dodecyl sulfate–polyacrylamide gel electrophoresis assays. We also performed ADP‐Glo assays for determining the total amount of adenosine triphosphate used in the kinase reaction. Unrelated DCM probands (109 males and 40 females) were enrolled in this study, of which 16 were familial and 133 sporadic. By mutation screening, a truncation variant of c1915‐1 g>t (p.Pro639Valfs*15) was identified, which was not detected in 400 chromosomes of 200 healthy volunteers; it is listed in the Human Genetic Variation Database with an allele frequency < 0.001. In the proband, the presence of mutations in known DCM‐causing genes was excluded with exome analysis. Familial analysis identified a 19‐year‐old male carrier who manifested slight left ventricular dilation with preserved systolic function. Phosphorylation assays analysed by Phos‐tag SDS‐PAGE revealed that the identified p.Pro639Valfs*15 mutation results in a complete lack of kinase activity, although it did not affect wild‐type cMLCK activity. ADP‐Glo assays confirmed that the mutant cMLCK had no kinase activity, whereas wild‐type cMLCK had a Km value of 5.93 ± 1.47 μM and a V max of 1.28 ± 0.03 mol/min/mol kinase. Conclusions These results demonstrate that a truncation mutation in the cMLCK gene p.Pro639Valfs*15 can be associated with significant impairment of MLC2v phosphorylation and possibly with development of DCM, although a larger study of DCM patients is required to determine the prevalence of this mutation and further strengthen its association with disease development.

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The effect of myosin light chain 2 dephosphorylation on Ca-sensitivity of force is enhanced in failing human hearts

Cited by 126 publications

References 34 publications

Altered myocardial force generation in end‐stage human heart failure

Altered myocardial force generation in end‐stage human heart failure

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy

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