Evidence map›Paper›PMID 39328062›Full record

ArticleCirculation research2024

Arg92Leu-cTnT Alters the cTnC-cTnI Interface Disrupting PKA-Mediated Relaxation.

Melissa L Lynn, Jesus Jimenez, Romi L Castillo, Catherine Vasquez, Mattie M Klass, Anthony P Baldo, Andrew Kim, Cyonna Gibson, Anne M Murphy, Jil C Tardiff

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Melissa L Lynn *Department of Biomedical Engineering (M.L.L., R.L.C., C.G., J.C.T.), University of Arizona, Tucson.ORCID 0000-0002-1107-4027
Jesus Jimenez *Department of Medicine, Division of Cardiology, Washington University at St. Louis, MO (J.J.).ORCID 0000-0001-5399-8538
Romi L CastilloDepartment of Biomedical Engineering (M.L.L., R.L.C., C.G., J.C.T.), University of Arizona, Tucson.ORCID 0000-0002-9383-7365
Catherine VasquezDepartment of Cellular and Molecular Medicine (C.V., J.C.T.), University of Arizona, Tucson.ORCID 0009-0004-7267-4079
Mattie M KlassDepartment of Physiological Sciences (A.K., M.M.K.), University of Arizona, Tucson.ORCID 0000-0003-2215-4345
Anthony P BaldoDepartment of Chemistry and Biochemistry (A.P.B.), University of Arizona, Tucson.ORCID 0009-0006-3683-8974
Andrew KimDepartment of Physiological Sciences (A.K., M.M.K.), University of Arizona, Tucson.ORCID 0009-0009-4655-1389
Cyonna GibsonDepartment of Biomedical Engineering (M.L.L., R.L.C., C.G., J.C.T.), University of Arizona, Tucson.
Anne M MurphyDepartment of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (A.M.M.).ORCID 0000-0001-9254-3202
Jil C TardiffDepartment of Biomedical Engineering (M.L.L., R.L.C., C.G., J.C.T.), University of Arizona, Tucson.

Funding

Integrative Approach to Divergent Remodeling in Thin Filament CardiomyopathiesR01HL075619 · NHLBI · UNIVERSITY OF ARIZONA · PI TARDIFF, JIL C · 2004 to 2025
$8.6M
The interaction of myosin and the thin filament: how mutations cause allosteric dysfunction and their connection to genetic cardiomyopathyR01HL107046 · NHLBI · UNIVERSITY OF ARIZONA · PI SCHWARTZ, STEVEN D, TARDIFF, JIL C · 2011 to 2023
$6.0M
NHLBI NIH HHS R01 HL075619NHLBI NIH HHS R01 HL107046
6 · The paper itself

Abstract

backgroundImpaired left ventricular relaxation, high filling pressures, and dysregulation of Ca

methodsHCM mutations R92L-cTnT (cardiac troponin T; Arg92Leu) and Δ160E-cTnT (Glu160 deletion) were studied in vivo, in vitro, and in silico via 2-dimensional echocardiography, Western blotting, ex vivo hemodynamics, stopped-flow kinetics, time-resolved fluorescence resonance energy transfer, and molecular dynamics simulations.

resultsThe HCM-causative mutations R92L-cTnT and Δ160E-cTnT result in different time-of-onset diastolic dysfunction. R92L-cTnT demonstrated early-onset diastolic dysfunction accompanied by a localized decrease in phosphorylation of cTnI. Constitutive phosphorylation of cTnI (cTnI-D

conclusionsThese data show that the early diastolic dysfunction observed in a subset of HCM is attributable to allosterically mediated structural changes at the cTnC-cTnI interface that impair accessibility of PKA, thereby blunting β-adrenergic responsiveness and identifying a potential molecular target for therapeutic intervention.

Indexed as

Cardiomyopathy, HypertrophicCyclic AMP-Dependent Protein KinasesTroponin ITroponin TAnimalsHumansMaleMiceMolecular Dynamics SimulationMutationTroponin CCyclic AMP-Dependent Protein KinasesTroponin CTroponin ITroponin Tcalciumcardiomyopathy, hypertrophicfluorescence resonance energy transfermolecular dynamics simulationphosphorylationsarcomerestroponin

Identifiers

PMID39328062
PMCPMC11502267

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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.