Role of myosin light chain phosphatase in cardiac physiology and pathophysiology

Chang, Audrey N.; Kamm, Kristine E.; Stull, James T.

doi:10.1016/j.yjmcc.2016.10.004

Cited by 30 publications

(36 citation statements)

References 123 publications

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“…A similar type of myosin II regulation occurs in non-muscle cells [3]. In cardiac striated muscle, RLC phosphorylation is constitutive and seems to be needed for the optimal contractility function [92].…”

Section: Is There Higher-order Organization Of Myosin II Filaments Inmentioning

confidence: 90%

Ordering of myosin II filaments driven by mechanical forces: experiments and theory

Dasbiswas

Schnorrer

et al. 2018

Phil. Trans. R. Soc. B

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Myosin II filaments form ordered superstructures in both cross-striated muscle and non-muscle cells. In cross-striated muscle, myosin II (thick) filaments, actin (thin) filaments and elastic titin filaments comprise the stereotypical contractile units of muscles called sarcomeres. Linear chains of sarcomeres, called myofibrils, are aligned laterally in registry to form cross-striated muscle cells. The experimentally observed dependence of the registered organization of myofibrils on extracellular matrix elasticity has been proposed to arise from the interactions of sarcomeric contractile elements (considered as force dipoles) through the matrix. Non-muscle cells form small bipolar filaments built of less than 30 myosin II molecules. These filaments are associated in registry forming superstructures ('stacks') orthogonal to actin filament bundles. Formation of myosin II filament stacks requires the myosin II ATPase activity and function of the actin filament crosslinking, polymerizing and depolymerizing proteins. We propose that the myosin II filaments embedded into elastic, intervening actin network (IVN) function as force dipoles that interact attractively through the IVN. This is in analogy with the theoretical picture developed for myofibrils where the elastic medium is now the actin cytoskeleton itself. Myosin stack formation in non-muscle cells provides a novel mechanism for the self-organization of the actin cytoskeleton at the level of the entire cell.This article is part of the theme issue 'Self-organization in cell biology'.

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Section: Is There Higher-order Organization Of Myosin II Filaments Inmentioning

confidence: 90%

Ordering of myosin II filaments driven by mechanical forces: experiments and theory

Dasbiswas

Schnorrer

et al. 2018

Phil. Trans. R. Soc. B

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“…Knockout of PP1c␤, but not PP1c␣ or PP1c␥, specifically in cardiac myocytes resulted in concentric remodeling, interstitial fibrosis, and contractile dysregulation with enhanced contractility of isolated myocytes and phosphorylation of RLC and myosin binding protein C (50). Cardiac RLC phosphorylation is not essential for contraction but does play an important role in enhancing contractile force to optimize cardiac performance (51)(52)(53) The severe phenotype with smooth muscle-specific knockout of PP1c␤ could be due to hyperphosphorylation of RLC and smooth muscle contracture, as expected for the loss of protein phosphatase activity directed to phosphorylated RLC. We measured increased RLC phosphorylation in untreated bladder tissues from PP1c␤ knockout mice snap-frozen in situ.…”

Section: Smooth Muscle Mlcpmentioning

confidence: 99%

The dominant protein phosphatase PP1c isoform in smooth muscle cells, PP1cβ, is essential for smooth muscle contraction

Chang

Gao²,

Liu³

et al. 2018

Journal of Biological Chemistry

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Contractile force development of smooth muscle is controlled by balanced kinase and phosphatase activities toward the myosin regulatory light chain (RLC). Numerous biochemical and pharmacological studies have investigated the specificity and regulatory activity of smooth muscle myosin light-chain phosphatase (MLCP) bound to myosin filaments and comprised of the regulatory myosin phosphatase target subunit 1 (MYPT1) and catalytic protein phosphatase 1cβ (PP1cβ) subunits. Recent physiological and biochemical evidence obtained with smooth muscle tissues from a conditional MYPT1 knockout suggests that a soluble, MYPT1-unbound form of PP1cβ may additionally contribute to myosin RLC dephosphorylation and relaxation of smooth muscle. Using a combination of isoelectric focusing and isoform-specific immunoblotting, we found here that more than 90% of the total PP1c in mouse smooth muscles is the β isoform. Moreover, conditional knockout of PP1cα or PP1cγ in adult smooth muscles did not result in an apparent phenotype in mice up to 6 months of age and did not affect smooth muscle contractions In contrast, smooth muscle-specific conditional PP1cβ knockout decreased contractile force development in bladder, ileal, and aortic tissues and reduced mouse survival. Bladder smooth muscle tissue from WT mice was selectively permeabilized to remove soluble PP1cβ to measure contributions of total (α-toxin treatment) and myosin-bound (Triton X-100 treatment) phosphatase activities toward phosphorylated RLC in myofilaments. Triton X-100 reduced PP1cβ content by 60% and the rate of RLC dephosphorylation by 2-fold. These results are consistent with the selective dephosphorylation of RLC by both MYPT1-bound and -unbound PP1cβ forms in smooth muscle.

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“…Nevertheless, the downregulated expression of myosin light chains Myl1, Myl4 , and Myl7 in response to ACE-I provides a molecular explanation for the improved cardiac contractility in the WT heart, previously reported by our group 8 , 19 . Indeed, overexpression of myosin light chain proteins has been shown to play an important role in hypertension, cardiac remodelling and hypertrophy 39 – 41 .…”

Section: Discussionmentioning

confidence: 99%

ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart

Yakubova

Thorrez

Svetlichnyy

et al. 2018

Sci Rep

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Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR−/−; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific pathways, while also activating cardioprotective mechanisms. We conclude that MetS and control murine hearts have unique transcriptional profiles and exhibit a partially specific transcriptional response to ACE-inhibition.

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Role of myosin light chain phosphatase in cardiac physiology and pathophysiology

Cited by 30 publications

References 123 publications

Ordering of myosin II filaments driven by mechanical forces: experiments and theory

Ordering of myosin II filaments driven by mechanical forces: experiments and theory

The dominant protein phosphatase PP1c isoform in smooth muscle cells, PP1cβ, is essential for smooth muscle contraction

ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart

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