ArticleProceedings of the National Academy of Sciences of the United States of America2014
Deleting titin's I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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60 citing papers in PubMed, 99 citations in OpenAlex.
- Titin's P-zone domains A164-167 are essential for thick filament structural arrangement.The Journal of general physiology · 2026Article
- Spatial control of myosin regulatory light chain phosphorylation modulates cardiac thick filament mechanosensing.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Titin Cardiomyopathy, Emerging Evidence: More Than A Big Heart.Current cardiology reports · 2025Review
- Archaic adaptive introgression in modern human reproductive genes.Communications biology · 2025Article
- Deregulated nutrient response in ttntv cardiomyopathy can be repaired via Erk inhibition for cardioprotective effects.Journal of molecular and cellular cardiology · 2025Article
- Novel Drug Targets in Diastolic Heart Disease.International journal of molecular sciences · 2025Review
- Exercise Training in Heart Failure: Clinical Benefits and Mechanisms.Circulation research · 2025Review
- The Heart Is a Smart Pump: Mechanotransduction Mechanisms of the Frank-Starling Law and the Anrep Effect.Annual review of physiology · 2025Review
- Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.iScience · 2024Article
- Allelic heterogeneity of TTNtv dilated cardiomyopathy can be modeled in adult zebrafish.JCI insight · 2024Article
- Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere.The Journal of clinical investigation · 2024Article
- Design Principles and Benefits of Spatially Explicit Models of Myofilament Function.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Molecular insights into titin's A-band.Journal of muscle research and cell motility · 2023Article
- Article
- Rbm20International journal of molecular sciences · 2022Article
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
- Use of animal models to understand titin physiology and pathology.Journal of cellular and molecular medicine · 2022Review
- Article
- Shortening the thick filament by partial deletion of titin's C-zone alters cardiac function by reducing the operating sarcomere length range.Journal of molecular and cellular cardiology · 2022Article
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11 authors at 1 institution in 1 country.
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Abstract
Titin, the largest protein known, forms a giant filament in muscle where it spans the half sarcomere from Z disk to M band. Here we genetically targeted a stretch of 14 immunoglobulin-like and fibronectin type 3 domains that comprises the I-band/A-band (IA) junction and obtained a viable mouse model. Super-resolution optical microscopy (structured illumination microscopy, SIM) and electron microscopy were used to study the thick filament length and titin's molecular elasticity. SIM showed that the IA junction functionally belongs to the relatively stiff A-band region of titin. The stiffness of A-band titin was found to be high, relative to that of I-band titin (∼ 40-fold higher) but low, relative to that of the myosin-based thick filament (∼ 70-fold lower). Sarcomere stretch therefore results in movement of A-band titin with respect to the thick filament backbone, and this might constitute a novel length-sensing mechanism. Findings disproved that titin at the IA junction is crucial for thick filament length control, settling a long-standing hypothesis. SIM also showed that deleting the IA junction moves the attachment point of titin's spring region away from the Z disk, increasing the strain on titin's molecular spring elements. Functional studies from the cellular to ex vivo and in vivo left ventricular chamber levels showed that this causes diastolic dysfunction and other symptoms of heart failure with preserved ejection fraction (HFpEF). Thus, our work supports titin's important roles in diastolic function and disease of the heart.
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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.