Post-translational modifications of myofilament proteins involved in length-dependent prolongation of relaxation in rabbit right ventricular myocardium

Monasky, Michelle M.; Taglieri, Domenico M.; Jacobson, Alice K.; Haizlip, Kaylan M.; Solaro, R. John; Janssen, Paul M. L.

doi:10.1016/j.abb.2012.10.005

Cited by 19 publications

(21 citation statements)

References 34 publications

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“…It has been shown by several groups that MLC-2v phosphorylation is also dependent on heart rate and stimulation frequency, suggesting a role for MLC-2v in frequency dependent activation (Lamberts et al, 2007; Varian and Janssen, 2007). In addition, MLC2v phosphorylation has also been shown to increase with stretch in cardiac muscle and recent studies have demonstrated its role in length-dependent activation (Monsasky et al, 2010; Monasky et al, 2013), highlighting a role for MLC-2v phosphorylation in regulatory aspects of cardiac output. Future studies investigating these regulatory mechanisms may also give further insights into the mechanisms regulating the altered myocardial growth response to pressure overload and decline of cardiac function in MLC-2v phosphorylation mutant mice.…”

Section: Ventricular Myosin Light Chain-2: Critical Phosphorylatiomentioning

confidence: 99%

Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease

Sheikh

Lyon

Chen

2015

Gene

124

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Myosin light chain-2 (MYL2, also called MLC-2) is an ∼19 kDa sarcomeric protein that belongs to the EF-hand calcium binding protein superfamily and exists as three major isoforms encoded by three distinct genes in mammalian striated muscle. Each of the three different MLC-2 genes (MLC-2f; fast twitch skeletal isoform, MLC-2v; cardiac ventricular and slow twitch skeletal isoform, MLC-2a; cardiac atrial isoform) has a distinct developmental expression pattern in mammals. Genetic loss-of-function studies in mice demonstrated an essential role for cardiac isoforms of MLC-2, MLC-2v and MLC-2a, in cardiac contractile function during early embryogenesis. In the adult heart, MLC-2v function is regulated by phosphorylation, which displays a specific expression pattern (high in epicardium and low in endocardium) across the heart. These data along with new data from computational models, genetic mouse models, and human studies have revealed a direct role for MLC-2v phosphorylation in cross-bridge cycling kinetics, calcium-dependent cardiac muscle contraction, cardiac torsion, cardiac function and various cardiac diseases. This review focuses on the regulatory functions of MLC-2 in the embryonic and adult heart, with an emphasis on phosphorylation-driven actions of MLC-2v in adult cardiac muscle, which provide new insights into mechanisms regulating myosin cycling kinetics and human cardiac diseases.

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Section: Ventricular Myosin Light Chain-2: Critical Phosphorylatiomentioning

confidence: 99%

Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease

Sheikh

Lyon

Chen

2015

Gene

124

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“…The lack of the Ca 2+ transient and mechanical relaxation coupling in time and our recent findings indicating the significance of TnI phosphorlyation to myocardial relaxation (Monasky et al 2010; Monasky et al 2013) necessitates further investigation into the role of both isolated and integrated thin filament PTMs on the regulation of myocardial relaxation.…”

Section: Introductionmentioning

confidence: 95%

“…After an increase in sarcomere/muscle length, force is changed in a near-immediate step (Mateja and de Tombe 2012), followed by a much slower process that takes minutes. This latter process involves a change in the calcium transient (Alvarez et al 1999; Luers et al 2005), as well as changes in myofilament phosphorylation events (Monasky et al 2010; Monasky et al 2013; Wijnker et al 2014). Combined, these changes further fine-tune the level of contractile activation, and prolong the relaxation at increased sarcomere/muscle length.…”

Section: Introductionmentioning

confidence: 99%

Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics

et al. 2014

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Cardiac muscle relaxation is an essential step in the cardiac cycle. Even when the contraction of the heart is normal and forceful, a relaxation phase that is too slow will limit proper filling of the ventricles. Relaxation is too often thought of as a mere passive process that follows contraction. However, many decades of advancements in our understanding of cardiac muscle relaxation have shown it is a highly complex and well-regulated process. In this review, we will discuss three distinct events that can limit the rate of cardiac muscle relaxation: the rate of intracellular calcium decline, the rate of thin-filament de-activation, and the rate of cross-bridge cycling. Each of these processes are directly impacted by a plethora of molecular events. In addition, these three processes interact with each other, further complicating our understanding of relaxation. Each of these processes is continuously modulated by the need to couple bodily oxygen demand to cardiac output by the major cardiac physiological regulators. Length-dependent activation, frequency-dependent activation, and β-adrenergic regulation all directly and indirectly modulate calcium decline, thin-filament deactivation, and cross-bridge kinetics. We hope to convey our conclusion that cardiac muscle relaxation is a process of intricate checks and balances, and should not be thought of as a single rate-limiting step that is regulated at a single protein level. Cardiac muscle relaxation is a system level property that requires fundamental integration of three governing systems: intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics.

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“…With regard to Starling’s law and length-dependent myofilament activation, while the mechanism remains a topic of research and debate [12, 15, 17, 34], studies by Monasky et al [50] have emphasized a role for downstream mechanisms in control of the prolonged relaxation occurring with preload-dependent increases in muscle length. Posttranslational modifications of myofilament proteins have been invoked as a cause for the length-dependent modulation of contractile dynamics [49]. Moreover, as pointed out by ter Keurs [66], the loss of adrenergic signaling in HF induces an increased reliance of the heart on the Frank-Starling relation with the potential of the elevated end-diastolic pressures to exacerbate coronary flow abnormalities.…”

Section: Introduction and Scopementioning

confidence: 99%

Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death

Yar

Monasky

Solaro

2014

Pflugers Arch - Eur J Physiol

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In this review, we address the following question: Are modifications at the level of sarcomeric proteins in acquired heart failure early inducers of altered cardiac dynamics and signaling leading to remodeling and progression to decompensation? There is no doubt that most inherited cardiomyopathies are caused by mutations in proteins of the sarcomere. We think this linkage indicates that early changes at the level of the sarcomeres in acquired cardiac disorders may be significant in triggering the progression to failure. We consider evidence that there are rate-limiting mechanisms downstream of the trigger event of Ca2+ binding to troponin C, which control cardiac dynamics. We discuss new perspectives on how modifications in these mechanisms may be of relevance to redox signaling in diastolic heart failure, to angiotensin II signaling via β-arrestin, and to remodeling related to altered structural rigidity of tropomyosin. We think that these new perspectives provide a rationale for future studies directed at a more thorough understanding of the question driving our review.

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Post-translational modifications of myofilament proteins involved in length-dependent prolongation of relaxation in rabbit right ventricular myocardium

Cited by 19 publications

References 34 publications

Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease

Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease

Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics

Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death

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