Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

Yadav, Sunil Kumar; Szczesna‐Cordary, Danuta

doi:10.1007/s12551-017-0248-8

Cited by 15 publications

(9 citation statements)

References 87 publications

(96 reference statements)

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“…RLC phosphorylation levels are significantly reduced in heart failure patients [ 82 , 83 , 84 ]. Animals in which myocardial infarction is induced by left anterior descending coronary artery ligation display a variation in the changes of RLC phosphorylation levels during heart failure progression.…”

Section: The Role Of Regulatory Light Chains In Normal and Diseased Heartsmentioning

confidence: 99%

Regulatory Light Chains in Cardiac Development and Disease

Markandran

Poh

Ferenczi

et al. 2021

IJMS

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The role of regulatory light chains (RLCs) in cardiac muscle function has been elucidated progressively over the past decade. The RLCs are among the earliest expressed markers during cardiogenesis and persist through adulthood. Failing hearts have shown reduced RLC phosphorylation levels and that restoring baseline levels of RLC phosphorylation is necessary for generating optimal force of muscle contraction. The signalling mechanisms triggering changes in RLC phosphorylation levels during disease progression remain elusive. Uncovering this information may provide insights for better management of heart failure patients. Given the cardiac chamber-specific expression of RLC isoforms, ventricular RLCs have facilitated the identification of mature ventricular cardiomyocytes, opening up possibilities of regenerative medicine. This review consolidates the standing of RLCs in cardiac development and disease and highlights knowledge gaps and potential therapeutic advancements in targeting RLCs.

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Section: The Role Of Regulatory Light Chains In Normal and Diseased Heartsmentioning

confidence: 99%

Regulatory Light Chains in Cardiac Development and Disease

Markandran

Poh

Ferenczi

et al. 2021

IJMS

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“…It is widely accepted that myofilament Ca 2+ sensitivity is regulated via phosphorylation of troponin I (TnI) at Ser 23 and 24 [ 6 , 7 , 8 ]. The phosphorylation of other proteins, such as myosin binding protein C [ 9 ] and regulatory light chain of myosin, also can modulate Ca 2+ sensitivity [ 10 , 11 , 12 ] but to a lesser degree.…”

Section: Introductionmentioning

confidence: 99%

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Vikhorev

Vikhoreva

2018

IJMS

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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.

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“…The N‐terminal domain of the human ventricular RLC contains a divalent cation binding site and a myosin light chain kinase (MLCK)‐specific phosphorylation site at Ser‐15 . A wealth of studies indicate that phosphorylation of myosin RLC is critical for the normal function of the heart, and that the myocardium containing dephosphorylated RLC has a reduced ability to produce force and maintain cardiac function at physiological levels (reviewed in ). Significantly depressed RLC phosphorylation was reported in heart failure (HF) patients and was also observed in experimental animal models of cardiac disease .…”

Section: Introductionmentioning

confidence: 99%

Phosphomimetic‐mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain

et al. 2018

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Myosin regulatory light chain (RLC) phosphorylation is important for cardiac muscle mechanics/function as well as for the Ca2+-troponin/tropomyosin regulation of muscle contraction. This study focuses on the arginine to glutamine (R58Q) substitution in the human ventricular RLC (MYL2 gene), linked to malignant hypertrophic cardiomyopathy in humans and causing severe functional abnormalities in transgenic R58Q mice, including inhibition of cardiac RLC phosphorylation. Using a phosphomimic recombinant RLC variant where the phosphorylation site Ser-15 was substituted with an aspartic acid (S15D) and placed in the background of R58Q, we aimed to assess whether we could rescue/mitigate R58Q-induced structural/functional abnormalities in vitro. We show rescue of several R58Q-exerted adverse phenotypes in S15D-R58Q-reconstituted porcine cardiac muscle preparations. A low level of maximal isometric force observed for R58Q- versus WT-reconstituted fibers was restored by S15D-R58Q. Significant beneficial effects were also observed on the Vmax of actin-activated myosin ATPase activity in S15D-R58Q versus R58Q-reconstituted myosin, along with its binding to fluorescently-labeled actin. We also report that R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in transgenic mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate. Experiments in S15D-R58Q-reconstituted porcine fibers showed a mild destabilization of the SRX state, suggesting an S15D-mediated shift in disordered-relaxed (DRX)↔SRX equilibrium towards the DRX state of myosin. Our study shows that S15D-phosphomimic can be used as a potential rescue strategy to abrogate/alleviate the RLC mutation-induced phenotypes and is a likely candidate for therapeutic intervention in HCM patients.

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Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

Cited by 15 publications

References 87 publications

Regulatory Light Chains in Cardiac Development and Disease

Regulatory Light Chains in Cardiac Development and Disease

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Phosphomimetic‐mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain

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