ArticleCirculation2022
Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy.
Article in Circulation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 48 citations in OpenAlex.
- Heart-on-a-chip and vasculature-on-a-chip platforms as models of cardiovascular disease.Nature reviews. Cardiology · 2026Review
- Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling.Circulation research · 2026Article
- Signaling pathway alterations in hearts of a porcine model harboring a β-myosin heavy chain (MYH7-R403Q) gene variant.Journal of molecular and cellular cardiology plus · 2025Article
- Human-Induced Pluripotent Stem Cell Models for Amyloid Cardiomyopathy: From Mechanistic Insights to Therapeutic Discovery.Journal of cardiovascular development and disease · 2025Review
- Stem cell-derived heterocellular atrial engineered cardiac tissue with comparisons to native human atrial myocardium.American journal of physiology. Heart and circulatory physiology · 2025Article
- Missense variants in the myosin binding domains ofbioRxiv : the preprint server for biology · 2025Article
- SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR-IRX transcription factor signaling axis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Unlocking the secrets of Cardiac development and function: the critical role of FHL2.Molecular and cellular biochemistry · 2025Review
- The role of mechanosignaling in the control of myocardial mass.American journal of physiology. Heart and circulatory physiology · 2025Review
- UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.Nature immunology · 2024Article
- Investigating Inherited Heart Diseases Using Human Induced Pluripotent Stem Cell-Based Models.Life (Basel, Switzerland) · 2024Review
- In defense of Huxley.Biophysical journal · 2024Article
- Applications, challenges, and prospects of induced pluripotent stem cells for vascular disease.Molecules and cells · 2024Review
- UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.Research square · 2024Article
- Engineered heart tissue: Design considerations and the state of the art.Biophysics reviews · 2024Review
- Modeling cardiomyocyte signaling and metabolism predicts genotype-to-phenotype mechanisms in hypertrophic cardiomyopathy.Computers in biology and medicine · 2024Article
- Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.International journal of molecular sciences · 2024Article
- Multiplexed Functional Assessments ofCirculation. Genomic and precision medicine · 2024Article
Corrections and comments
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Authors and funding
23 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundFamilial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics.
methodsOur discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations.
resultsEnhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (
conclusionsOur studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.
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