ArticleCardiovascular research2022
Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation.
Article in Cardiovascular research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis.Frontiers in cardiovascular medicine · 2022Pooled it
- Calcium handling remodeling in dilated cardiomyopathy: From molecular mechanisms to targeted therapies.Channels (Austin, Tex.) · 2025Review
- Living myocardial slices retain patient-specific features: Insights into etiology and therapeutic history.JHLT open · 2025Article
- Obscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias.The Journal of general physiology · 2025Article
- Next generation sequencing in dilated cardiomyopathy: utility and challenges in the African context.Frontiers in cardiovascular medicine · 2025Review
- Review
- Prevention and treatment of peri-implant fibrosis by functionally inhibiting skeletal cells expressing the leptin receptor.Nature biomedical engineering · 2024Article
- What Do We Know about Peripartum Cardiomyopathy? Yesterday, Today, Tomorrow.International journal of molecular sciences · 2024Review
- Proteomics of the heart.Physiological reviews · 2024Review
- Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies.Biomedicines · 2024Review
- RNA-Binding Proteins in Cardiomyopathies.Journal of cardiovascular development and disease · 2024Review
- Depressed myocardial cross-bridge cycling kinetics in a female guinea pig model of diastolic heart failure.The Journal of general physiology · 2023Article
- Sarcomere length affects Ca2+ sensitivity of contraction in ischemic but not non-ischemic myocardium.The Journal of general physiology · 2023Article
- [Recent studies on dilated cardiomyopathy caused byZhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2023Review
- Identification ofDiagnostics (Basel, Switzerland) · 2023Article
- Affimers targeting proteins in the cardiomyocyte Z-disc: Novel tools that improve imaging of heart tissue.Frontiers in cardiovascular medicine · 2023Article
- KLF13 Loss-of-Function Mutations Underlying Familial Dilated Cardiomyopathy.Journal of the American Heart Association · 2022Article
- Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.Circulation · 2022Article
- Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study.Metabolites · 2022Article
- Dilated cardiomyopathy: a new insight into the rare but common cause of heart failure.Heart failure reviews · 2022Review
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12 authors at 6 institutions in 3 countries.
Funding
Abstract
aimsDilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterizations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants. METHODS AND
resultsWe isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified down-regulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was up-regulated in DCM patients with TTN-truncating variants.
conclusionTitin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.
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