Cardiac myosin regulatory light chain kinase modulates cardiac contractility by phosphorylating both myosin regulatory light chain and troponin I

Sevrieva, Ivanka; Brandmeier, Birgit; Ponnam, Saraswathi; Gautel, Mathias; Irving, Malcolm; Campbell, Kenneth S.; Sun, Yin-Biao; Kampourakis, Thomas

doi:10.1074/jbc.ra119.011945

Cited by 21 publications

(23 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We interpret the biosensor FRET transient as reporting TnC's global conformational change, from extended to compact, during the twitch, as based on extensive in vitro work on TnC [17,36,53,54]. During a twitch, we posit that the TnC-tethered FRET probes Clover (donor) and mRuby2 (acceptor) move closer together, consistent with the increased FRET signal observed.…”

Section: Discussionmentioning

confidence: 53%

Sarcomere integrated biosensor detects myofilament-activating ligands in real time during twitch contractions in live cardiac muscle

Vetter

Martin

Thompson

et al. 2020

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

The sarcomere is the functional unit of cardiac muscle, essential for normal heart function. To date, it has not been possible to study, in real time, thin filament-based activation dynamics in live cardiac muscle. We report here results from a cardiac troponin C (TnC) FRET-based biosensor integrated into the cardiac sarcomere via stoichiometric replacement of endogenous TnC. The TnC biosensor provides, for the first time, evidence of multiple thin filament activating ligands, including troponin I interfacing with TnC and cycling myosin, during a cardiac twitch. Results show that the TnC FRET biosensor transient significantly precedes that of peak twitch force. Using small molecules and genetic modifiers known to alter sarcomere activation, independently of the intracellular Ca 2+ transient, the data show that the TnC biosensor detects significant effects of the troponin I switch domain as a sarcomere-activating ligand. Interestingly, the TnC biosensor also detected the effects of load-dependent altered myosin cycling, as shown by a significant delay in TnC biosensor transient inactivation during the isometric twitch. In addition, the TnC biosensor detected the effects of myosin as an activating ligand during the twitch by using a small molecule that directly alters cross-bridge cycling, independently of the intracellular Ca 2+ transient. Collectively, these results aid in illuminating the basis of cardiac muscle contractile activation with implications for gene, protein, and small molecule-based strategies designed to target the sarcomere in regulating beat-to-beat heart performance in health and disease.

show abstract

Section: Discussionmentioning

confidence: 53%

Sarcomere integrated biosensor detects myofilament-activating ligands in real time during twitch contractions in live cardiac muscle

Vetter

Martin

Thompson

et al. 2020

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…Structural insights into the IHM and SRX are supported by functional measurements in isolated trabecular muscle, where it has been shown that cRLC phosphorylation increased the rate of force re-development after muscle release ( Sevrieva et al, 2020 and Toepfer et al, 2016b ). This result inferred that the mechanism of action of RLC phosphorylation is the increase in Huxley's N a parameter, which is consistent with a reduction of SRX and increase in DRX myosin states ( Craig et al, 1987 ; Nag et al, 2017 ; Toepfer et al, 2016b ).…”

Section: Regulation Of Myosin Srx By Protein Level Phosphorylation Amentioning

confidence: 97%

Cardiac myosin super relaxation (SRX): a perspective on fundamental biology, human disease and therapeutics

Schmid

Toepfer

2021

Biology Open

View full text Add to dashboard Cite

The fundamental basis of muscle contraction ‘the sliding filament model’ (Huxley and Niedergerke, 1954; Huxley and Hanson, 1954) and the ‘swinging, tilting crossbridge-sliding filament mechanism’ (Huxley, 1969; Huxley and Brown, 1967) nucleated a field of research that has unearthed the complex and fascinating role of myosin structure in the regulation of contraction. A recently discovered energy conserving state of myosin termed the super relaxed state (SRX) has been observed in filamentous myosins and is central to modulating force production and energy use within the sarcomere. Modulation of myosin function through SRX is a rapidly developing theme in therapeutic development for both cardiovascular disease and infectious disease. Some 70 years after the first discoveries concerning muscular function, modulation of myosin SRX may bring the first myosin targeted small molecule to the clinic, for treating hypertrophic cardiomyopathy (Olivotto et al., 2020). An often monogenic disease HCM afflicts 1 in 500 individuals, and can cause heart failure and sudden cardiac death. Even as we near therapeutic translation, there remain many questions about the governance of muscle function in human health and disease. With this review, we provide a broad overview of contemporary understanding of myosin SRX, and explore the complexities of targeting this myosin state in human disease.This article has an associated Future Leaders to Watch interview with the authors of the paper.

show abstract

“…As cardiac MLCK contains an autoregulatory segment, it is likely to play a role similar to those of smMLCK and skMLCK. Most studies showed that MLCK is an RLC-dedicated kinase [ 95 ] until a recent study showed that human MLCK phosphorylates both RLC and troponin I (TnI) [ 96 ]. The following questions remain: (1) What are the roles of other kinases?…”

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

View full text Add to dashboard Cite

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.

show abstract

Cardiac myosin regulatory light chain kinase modulates cardiac contractility by phosphorylating both myosin regulatory light chain and troponin I

Cited by 21 publications

References 44 publications

Sarcomere integrated biosensor detects myofilament-activating ligands in real time during twitch contractions in live cardiac muscle

Sarcomere integrated biosensor detects myofilament-activating ligands in real time during twitch contractions in live cardiac muscle

Cardiac myosin super relaxation (SRX): a perspective on fundamental biology, human disease and therapeutics

Regulatory Light Chains in Cardiac Development and Disease

Contact Info

Product

Resources

About