ArticleCirculation2014
Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole.
Article in Circulation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers, 2 of them syntheses that pooled it.
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Who cites it
107 citing papers in PubMed, 2 syntheses or guidelines pooled it, 141 citations in OpenAlex.
- Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis.Frontiers in cardiovascular medicine · 2022Pooled it
- Left Ventricular Speckle Tracking-Derived Cardiac Strain and Cardiac Twist Mechanics in Athletes: A Systematic Review and Meta-Analysis of Controlled Studies.Sports medicine (Auckland, N.Z.) · 2017Pooled it
- Diastolic contributors in cardiomyocytes of a cardiometabolic HFpEF-like mouse model.The Journal of general physiology · 2026Article
- The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch.eLife · 2026Article
- Cytoplasmic RBM20 granules modulate non-RBM20 target splicing through interactions with other splicing factors.Nucleic acids research · 2026Article
- Transcriptome Reprogramming in Heart Failure: The Hidden Splicing Code.Current cardiology reports · 2026Review
- RBM20 isoform regulation by independent transcription start sites adapts alternative splicing in development and disease.Nature communications · 2026Article
- Human atrial skinned muscle fibers exhibit reduced length-dependent activation but show faster force development kinetics than ventricular muscle.Journal of molecular and cellular cardiology · 2026Article
- Functional Validation of a Novel HomozygousHuman mutation · 2026Article
- Rbm20 antisense oligonucleotides alleviate diastolic dysfunction in a mouse model of cardiometabolic heart failure (HFpEF).Cardiovascular research · 2025Article
- What Is Cardiometabolic HFpEF and How Can We Study it Preclinically?JACC. Basic to translational science · 2025Review
- Reducing Granules Without Splicing Restoration Alleviates RBM20 Cardiomyopathy.Circulation research · 2025Article
- Antisense-mediated regulation of exon usage in the elastic spring region of Titin modulates sarcomere function.Cardiovascular research · 2025Article
- Profiling of RBM20-Regulated CaMKIIδ Splice Variants Across the Heart, Skeletal Muscle, and Olfactory Bulbs.Genes to cells : devoted to molecular & cellular mechanisms · 2025Article
- CaJournal of molecular and cellular cardiology · 2025Article
- Alternative splicing factors and cardiac disease: more than just missplicing?RNA (New York, N.Y.) · 2025Article
- An overview of insights and updates on TTN mutations in cardiomyopathies.Frontiers in pharmacology · 2025Review
- Alternative Splicing in the Heart: The Therapeutic Potential of Regulating the Regulators.International journal of molecular sciences · 2024Review
- Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems.Circulation. Genomic and precision medicine · 2024Review
- Cardiac splicing as a diagnostic and therapeutic target.Nature reviews. Cardiology · 2023Review
47 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
backgroundExperimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. METHODS AND
resultsCompliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(ΔRRM)mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20(ΔRRM)mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20(ΔRRM) hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20(ΔRRM) mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice.
conclusionsTitin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.
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Registered trials
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.