ArticleThe Journal of general physiology2021
Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.
Article in The Journal of general physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Missense variants in the myosin binding domains ofbioRxiv : the preprint server for biology · 2025Article
- 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
- The transmission of mutation effects in a multiprotein machine: A comprehensive metadynamics study of the cardiac thin filament.Protein science : a publication of the Protein Society · 2024Article
- 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
- 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
- Super-relaxed or super-stressed: Modeling length-dependent activation in cardiac muscle.Biophysical journal · 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
- Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.PNAS nexus · 2023Article
- Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy.Scientific reports · 2022Article
- Review
- Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2022Review
- Prospects for remodeling the hypertrophic heart with myosin modulators.Frontiers in cardiovascular medicine · 2022Review
- Cardiac myosin contraction and mechanotransduction in health and disease.The Journal of biological chemistry · 2021Review
- Ion Channel Impairment and Myofilament CaCells · 2021Review
- A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.Molecular biology of the cell · 2021Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.
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