ArticleBiochimica et biophysica acta. Molecular basis of disease2017
Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner.
Article in Biochimica et biophysica acta. Molecular basis of disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort.International journal of molecular sciences · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Novel Genetic Variants Associated with Diabetic Neuropathy Risk in Type 2 Diabetes: A Whole-Exome Sequencing Approach.International journal of molecular sciences · 2025Article
- Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.Nature genetics · 2024Article
- Titin: roles in cardiac function and diseases.Frontiers in physiology · 2024Review
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
- Article
- RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Dilated cardiomyopathy: a new insight into the rare but common cause of heart failure.Heart failure reviews · 2022Review
- Protein Quality Control at the Sarcomere: Titin Protection and Turnover and Implications for Disease Development.Frontiers in physiology · 2022Review
- RBM20, a Therapeutic Target to Alleviate Myocardial StiffnessFrontiers in cardiovascular medicine · 2022Review
- Coordination of RNA Processing Regulation by Signal Transduction Pathways.Biomolecules · 2021Review
- RBM20-Mediated Pre-mRNA Splicing Has Muscle-Specificity and Differential Hormonal Responses between Muscles and in Muscle Cell Cultures.International journal of molecular sciences · 2021Article
- Herbal cake-partitioned moxibustion inhibits colonic autophagy in Crohn's diseaseWorld journal of gastroenterology · 2020Article
- New Insights in RBM20 Cardiomyopathy.Current heart failure reports · 2020Review
- Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure.Journal of clinical medicine · 2020Review
- Review
- Effects of Adiponectin on Diastolic Function in Mice Underwent Transverse Aorta Constriction.Journal of cardiovascular translational research · 2020Article
- Article
- Compliant Titin Isoform Content Is Reduced in Left Ventricles of Sedentary Versus Active Rats.Frontiers in physiology · 2020Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Titin, a giant sarcomeric protein, is largely responsible for the diastolic properties of the heart. It has two major isoforms, N2B and N2BA due to pre-mRNA splicing regulated mainly by a splicing factor RNA binding motif 20 (RBM20). Mis-splicing of titin pre-mRNA in response to external stimuli may lead to altered ratio of N2B to N2BA, and thus, impaired cardiac contractile function. However, little is known about titin alternative splicing in response to external stimuli. Here, we reported the detailed mechanisms of titin alternative splicing in response to insulin. Insulin treatment in cultured neonatal rat cardiomyocytes (NRCMs) activated the PI3K-Akt-mTOR kinase axis, leading to increased N2B expression in the presence of RBM20, but not in NRCMs in the absence of RBM20. By inhibiting this kinase axis with inhibitors, decreased N2B isoform was observed in NRCMs and also in diabetic rat model treated with streptozotocin, but not in NRCMs and diabetic rats in the absence of RBM20. In addition to the alteration of titin isoform ratios in response to insulin, we found that RBM20 expression was increased in NRCMs with insulin treatment, suggesting that RBM20 levels were also regulated by insulin-induced kinase axis. Further, knockdown of p70S6K1 with siRNA reduced both RBM20 and N2B levels, while knockdown of 4E-BP1 elevated expression levels of RBM20 and N2B. These findings reveal a major signal transduction pathway for insulin-induced titin alternative splicing, and place RBM20 in a central position in the pathway, which is consistent with the reputed role of RBM20 in titin alternative splicing. Findings from this study shed light on gene therapeutic strategies at the molecular level by correction of pre-mRNA mis-splicing.
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