ArticleMolecular biology of the cell2021
A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.
Article in Molecular biology of the cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- Article
- Actomyosin-Based Nanodevices for Sensing and Actuation: Bridging Biology and Bioengineering.Biosensors · 2025Review
- Danicamtiv reduces myosin's working stroke but activates the thin filament by accelerating actomyosin attachment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dilated cardiomyopathy-associated skeletal muscle actin (ACTA1) mutation R256H disrupts actin structure and function and causes cardiomyocyte hypocontractility.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Focus on cardiac troponin complex: From gene expression to cardiomyopathy.Genes & diseases · 2024Review
- Danicamtiv reduces myosin's working stroke but enhances contraction by activating the thin filament.bioRxiv : the preprint server for biology · 2024Article
- Structural dynamics of the intrinsically disordered linker region of cardiac troponin T.bioRxiv : the preprint server for biology · 2024Article
- Insights into posttranslational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP.Journal of applied physiology (Bethesda, Md. : 1985) · 2024Article
- Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T.bioRxiv : the preprint server for biology · 2024Article
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
- Single-molecule mechanics and kinetics of cardiac myosin interacting with regulated thin filaments.Biophysical journal · 2023Article
- Functional assays reveal the pathogenic mechanism of a de novo tropomyosin variant identified in patient with dilated cardiomyopathy.Journal of molecular and cellular cardiology · 2023Article
- Effects of Sarcomere Activators and Inhibitors Targeting Myosin Cross-Bridges on CaMolecular pharmacology · 2022Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Dilated cardiomyopathy (DCM) is a significant cause of pediatric heart failure. Mutations in proteins that regulate cardiac muscle contraction can cause DCM; however, the mechanisms by which molecular-level mutations contribute to cellular dysfunction are not well understood. Better understanding of these mechanisms might enable the development of targeted therapeutics that benefit patient subpopulations with mutations that cause common biophysical defects. We examined the molecular- and cellular-level impacts of a troponin T variant associated with pediatric-onset DCM, R134G. The R134G variant decreased calcium sensitivity in an in vitro motility assay. Using stopped-flow and steady-state fluorescence measurements, we determined the molecular mechanism of the altered calcium sensitivity: R134G decouples calcium binding by troponin from the closed-to-open transition of the thin filament and decreases the cooperativity of myosin binding to regulated thin filaments. Consistent with the prediction that these effects would cause reduced force per sarcomere, cardiomyocytes carrying the R134G mutation are hypocontractile. They also show hallmarks of DCM that lie downstream of the initial insult, including disorganized sarcomeres and cellular hypertrophy. These results reinforce the importance of multiscale studies to fully understand mechanisms underlying human disease and highlight the value of mechanism-based precision medicine approaches for DCM.
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