ArticleCirculation research2022
GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation.
Article in Circulation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05993585 (The Effects of Cardiac Resynchronisation Therapy on the Frank Starling Mechanism in Patients With Heart Failure), which is not on this map. Cited by 12 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Effects of Cardiac Resynchronisation Therapy on the Frank Starling Mechanism in Patients With Heart Failure
Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Big Job for the Small Titin: Don't Underestimate the "Little" Guy.Circulation research · 2026Article
- Modeling the interplay of sex hormones in cardiac hypertrophic signaling.PLoS computational biology · 2025Article
- GSK3β-driven phosphorylation of ABLIM1 regulates its interactions with titin cardiac muscle.The Journal of general physiology · 2025Article
- Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation.American journal of physiology. Heart and circulatory physiology · 2024Article
- Mitochondrial Kinase Signaling for Cardioprotection.International journal of molecular sciences · 2024Review
- Pterostilbene attenuates heart failure by inhibiting myocardial ferroptosis through SIRT1/GSK-3β/GPX4 signaling pathway.Heliyon · 2024Article
- A novel mutation of glycogen synthase kinase-3β leads to a reduced level of GSK3β protein in a patient with dilated cardiomyopathy.Genes & diseases · 2024Article
- GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit.Biochimica et biophysica acta. Molecular basis of disease · 2023Review
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- The role of β-catenin in cardiac diseases.Frontiers in pharmacology · 2023Review
- Small Angle X-ray Diffraction as a Tool for Structural Characterization of Muscle Disease.International journal of molecular sciences · 2022Review
- Actin-Binding LIM 1 (ABLIM1) Inhibits Glioblastoma Progression and Serves as a Novel Prognostic Biomarker.Disease markers · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
16 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundAltered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β's in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance.
methodsInducible cardiomyocyte-specific GSK-3β knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied.
resultsSkinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3β. Agreeing with the localization of its targets, GSK-3β that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3β in neonatal rat ventricular cardiomyocytes. One of GSK-3β's z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3β. Last, GSK-3β myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA.
conclusionsWe identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3β levels were reduced in patients with heart failure, indicating z-disc localized GSK-3β is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.