Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations

Kazmierczak, Katarzyna; Yuan, Chen-Ching; Liang, Jingsheng; Huang, Wenrui; Rojas, Ana I.; Szczesna‐Cordary, Danuta

doi:10.3389/fphys.2014.00353

Cited by 14 publications

(25 citation statements)

References 68 publications

(124 reference statements)

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“…However, the lack of the N-terminal extension is not necessarily detrimental for muscle function (42). Absence of the N-terminal extension generates lower force (41), probably causing a less prominent power stroke in S1A2, and is not related to abnormal cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain

Guhathakurta

Próchniewicz

Thomas

2015

Proc. Natl. Acad. Sci. U.S.A.

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We have used time-resolved fluorescence resonance energy transfer (TR-FRET) to determine the role of myosin essential light chains (ELCs) in structural transitions within the actomyosin complex. Skeletal muscle myosins have two ELC isoforms, A1 and A2, which differ by an additional 40-45 residues at the N terminus of A1, and subfragment 1 (S1) containing A1 (S1A1) has higher catalytic efficiency and higher affinity for actin than S1A2. ELC's location at the junction between the catalytic and light-chain domains gives it the potential to play a central role in the force-generating power stroke. Therefore, we measured site-directed TR-FRET between a donor on actin and an acceptor near the C terminus of ELC, detecting directly the rotation of the light-chain domain (lever arm) relative to actin (power stroke), induced by the interaction of ATPbound myosin with actin. TR-FRET resolved the weakly bound (W) and strongly bound (S) states of actomyosin during the W-to-S transition (power stroke). We found that the W states are essentially the same for the two isoenzymes, but the S states are quite different, indicating a much larger movement of S1A1. FRET from actin to a probe on the N-terminal extension of A1 showed close proximity to actin. We conclude that the N-terminal extension of A1-ELC modulates the W-to-S structural transition of acto-S1, so that the light-chain domain undergoes a much larger power stroke in S1A1 than in S1A2. These results have profound implications for understanding the contractile function of actomyosin, as needed in therapeutic design for muscle disorders.muscle | actomyosin | light chains | fluorescence resonance energy transfer A central challenge in the biophysics of motility is to understand the molecular mechanisms of structural transitions in the actomyosin ATPase (enzyme code 3.6.4.1) cycle, in which myosin alters its affinity for actin in a nucleotide-dependent manner from weak (W) actin-binding states (with ATP or ADP-P i bound to the myosin active site) to strong (S) actin-binding states (with ADP or no nucleotide, i.e., rigor), resulting in the generation of force. It is particularly important to obtain direct information about the structural dynamics of the whole actomyosin complex, because there is evidence that each protein, when studied separately, undergoes changes in structure and dynamics during transitions from the W to S states (1-5). S states are relatively stable and easy to study, but the W actomyosin complex is less accessible to study, due to its transient and structurally dynamic nature.The myosin heavy chain starts with the N-terminal catalytic domain (CD), which contains the nucleotide-binding pocket and the actin-binding site. A small converter region connects the CD to an extended α-helical segment that forms the core of the lightchain domain (LCD) (6, 7). The LCD contains two IQ motifs that serve as binding sites for one essential light chain (ELC) and one regulatory light chain (RLC) and is proposed to function as a lever arm that amplifies small structural c...

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Section: Discussionmentioning

confidence: 99%

Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain

Guhathakurta

Próchniewicz

Thomas

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The steady state force of exercised A57G mice was significantly lower than in WT, which in combination with decreased Ca 2+ sensitivity could indicate a potential for heart failure (Table 1) (Huang 2015). As shown in Kazmierczak et al (2014), no significant changes in endogenous MyBP-C, Tm, TnT, TnI, or RLC phosphorylation were found in sedentary or exercised A57G-ELC animals compared to WT-ELC mice. The lack of the effect of exercise on protein phosphorylation was somewhat surprising but the similar observations have been reported by other laboratories and no effect of exercise on phosphorylation of myosin RLC in the ventricles or atria of mice was found by Fewell et al (1997).…”

Section: Functional Effects Of Mlc Mutationsmentioning

confidence: 67%

“…Furthermore, the A57G-ELC mutation was reported to cause SCD in humans (Lee et al 2001). Since SCD often happens after intense exercise, the effects of exercise of Tg-A57G versus Tg-WT mice were investigated (Kazmierczak et al 2014). Compared to the sedentary group, in which only SERCA2a was upregulated in A57G versus WT mice, quantitative PCR results showed that the HCM-related genes, e.g.…”

Section: Functional Effects Of Mlc Mutationsmentioning

confidence: 99%

“…atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and Col VIIIa (collagen) were all upregulated in exercised A57G-ELC mice (Table 1). On the other hand, studies on sedentary and exercised mouse fibers showed a significant decrease in calcium sensitivity of force in exercised vs. sedentary A57G-ELC mice (Kazmierczak et al 2014). The steady state force of exercised A57G mice was significantly lower than in WT, which in combination with decreased Ca 2+ sensitivity could indicate a potential for heart failure (Table 1) (Huang 2015).…”

Section: Functional Effects Of Mlc Mutationsmentioning

confidence: 99%

“…Unlike RLC proteins, the ELC interacts with actin through its N-terminus (Sutoh 1982; Trayer and Trayer 1985; Winstanley et al 1977), and this interaction is hypothesized to be the molecular target for the ELC disease causing mechanisms (Kazmierczak et al 2009, 2014; Muthu et al 2011). We have previously shown that the N-terminally truncated Δ43-ELC was able to shift the cross bridge mass distribution toward the thin filament.…”

Section: Differences Between Rlc and Elc Phenotypesmentioning

confidence: 99%

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Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations

Huang

Szczesna‐Cordary

2015

J Muscle Res Cell Motil

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We discuss here the potential mechanisms of action associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathy causing mutations in the myosin regulatory (RLC) and essential (ELC) light chains. Specifically, we focus on four HCM mutations: RLC-A13T, RLC-K104E, ELC-A57G and ELC-M173V, and one DCM RLC-D94A mutation shown by population studies to cause different cardiomyopathy phenotypes in humans. Our studies indicate that RLC and ELC mutations lead to heart disease through different mechanisms with RLC mutations triggering alterations of the secondary structure of the RLC which further affect the structure and function of the lever arm domain and impose changes in the cross bridge cycling rates and myosin force generation ability. The ELC mutations exert their detrimental effects through changes in the interaction of the N-terminus of ELC with actin altering the cross talk between the thick and thin filaments and ultimately resulting in an altered force-pCa relationship. We also discuss the effect of mutations on myosin light chain phosphorylation. Exogenous myosin light chain phosphorylation and/or pseudo-phosphorylation were explored as potential rescue tools to treat hypertrophy-related cardiac phenotypes.

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Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains

Yadav

Sitbon

Kazmierczak

et al. 2019

Pflugers Arch - Eur J Physiol

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Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are amongst the leading causes of morbidity and mortality worldwide. Such genetically-driven forms of hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathies are chronic, debilitating diseases that result from biomechanical defects in cardiac muscle contraction and frequently progress to heart failure (HF). Locus and allelic heterogeneity, as well as clinical variability combined with genetic and phenotypic overlap between different cardiomyopathies, have challenged proper clinical prognosis and provided an incentive for identification of pathogenic variants. This review attempts to provide an overview of inherited cardiomyopathies with a focus on their genetic etiology in myosin regulatory (RLC) and essential (ELC) light chains, which are EF-hand protein family members with important structural and regulatory roles. From the clinical discovery of cardiomyopathy-linked light chain mutations in patients to an array of exploratory studies in animals, reconstituted, and recombinant systems, we have summarized the current state of knowledge on light chain mutations and how they induce physiological disease states via biochemical and biomechanical alterations at the molecular, tissue and organ level. Cardiac myosin RLC phosphorylation and the N-terminus ELC have been discussed as two important emerging modalities with important implications in the regulation of myosin motor function and thus cardiac performance. A comprehensive understanding of such triggers is absolutely necessary for the development of target-specific rescue strategies to ameliorate or reverse the effects of myosin light chain-related inherited cardiomyopathies.

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Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations

Cited by 14 publications

References 68 publications

Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain

Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain

Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations

Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains

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