Functional comparison of phosphomimetic S15D and T160D mutants of myosin regulatory light chain exchanged in cardiac muscle preparations of HCM and WT mice

Kazmierczak, Katarzyna; Liang, Jingsheng; Gomez-Guevara, Michelle; Szczesna‐Cordary, Danuta

doi:10.3389/fcvm.2022.988066

Cited by 6 publications

(30 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While MLC1 provides physical stability to myosin, MLC2 modulates myosin activity and facilitates the interaction of myosin with actin filaments. 19,20 Recent studies focusing on HCM-causing mutations in the genes encoding ELC (MYL3) 59 and RLC (MYL2) [60][61][62] have shown that these mutations can depopulate the SRX state, thereby suggesting that physical alterations to the light chains can change the structural state of myosin. Additionally, another layer of complexity to myosin's functionality is introduced by the phosphorylation process.…”

Section: Influence Of Myosin Light Chain Mutations and Phosphorylatio...mentioning

confidence: 99%

“…Not only does phosphorylation of MLC2 strengthen the interaction between myosin and actin 19,20 but it also facilitates the transition from the SRX to the DRX state. 21,22,61,62 Such phosphorylation events enhance the formation of force-producing crossbridges and amplify force generation. 19,63 Interestingly, an increase in MLC2 phosphorylation has been observed in HCM mouse models expressing the human A57G mutation in the MYL3 gene 59 and in human HCM hearts with the K280N mutation in the TNNT2 gene.…”

Section: Influence Of Myosin Light Chain Mutations and Phosphorylatio...mentioning

confidence: 99%

See 1 more Smart Citation

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect

Sequeira,

Maack,

Reil

et al. 2024

Circulation Research

View full text Add to dashboard Cite

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin—specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)—with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin’s SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.

show abstract

Section: Influence Of Myosin Light Chain Mutations and Phosphorylatio...mentioning

confidence: 99%

Section: Influence Of Myosin Light Chain Mutations and Phosphorylatio...mentioning

confidence: 99%

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect

Sequeira,

Maack,

Reil

et al. 2024

Circulation Research

View full text Add to dashboard Cite

show abstract

“…LVPM fibers were prepared as described earlier 18,19 . Briefly, muscle bundles were isolated from the hearts of experimental mice (wild type, Alport, and LDLR/P407) and then separated into…”

Section: Preparation Of Skinned Left Ventricular Papillary Muscle (Lv...mentioning

confidence: 99%

“…To estimate the number of myosin heads occupying the DRX versus SRX states in wild-type, Alport, and LDLR/P407 mice, Adenosine triphosphate (ATP) turnover measurements were performed using skinned LVPM, as previously described [18][19][20] . In these experiments, the fluorescent N-methylanthraniloyl (mant)-ATP was exchanged for nonfluorescent (dark) ATP in skinned LVPM fibers using the IonOptix instrument.…”

Section: Determination Of Proportion Of Myosin Heads Occupying the Dr...mentioning

confidence: 99%

“…Amplitudes of the fast (P1) and slow (P2) phases of fluorescence decay and their respective T1 and T2 lifetimes (in seconds) were derived from fits to a nonlinear least-squares algorithm in GraphPad PRISM version 10 (GraphPad Software, San Diego, CA, USA) [18][19][20] . T1 and T2 are the lifetimes of DRX and SRX states.…”

Section: Determination Of Proportion Of Myosin Heads Occupying the Dr...mentioning

confidence: 99%

See 1 more Smart Citation

Sarcomeric SRX:DRX Equilibrium in Alport and LDLR/P407 Mouse Models of HFpEF

Kamiar,

Williams,

Capcha

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Cardiac myosin energetic states that regulate heart contractility define interactions of myosin cross-bridges with actin-containing thin filaments have been functionally linked with the pathology of hypertrophic cardiomyopathy (HCM). In particular, the balance between the disordered relaxed (DRX) and super relaxed (SRX) states that correlate respectively with enhanced force and energy conservation significantly determine myocardial performance and energy utilization. Compelling evidence suggests that a balanced SRX and DRX states proportion is a prerequisite for long-term cardiac health. Whereas roles for altered SRX: DRX proportions in HCM have been studied in depth, the mechanics of sarcomeric dysfunction and SRX: DRX proportions have not been reported in models of acquired heart failure (HF) including HF with preserved ejection fraction (HFpEF). Here, we quantified SRX andDRX myosin populations in two mouse models of HFpEF, including Alport and LDLR/P407 mice that represent cardiorenal/hypertensive and cardiometabolic/hyperlipidemic mouse models of HFpEF, respectively. We report significant changes in the SRX:DRX in both HFpEF mouse models, with an increased DRX state associated with Alport mice and a stabilized SRX state associated with LDLR/P407 mice. These findings correlate respectively with the hypercontractility and metabolic dysregulation with bradycardia phenotypes.

show abstract