ArticleProceedings of the National Academy of Sciences of the United States of America2015
Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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62 citing papers in PubMed, 76 citations in OpenAlex.
- Modulating the myosin super-relaxed state as a therapeutic strategy for myosin light chain-linked cardiomyopathies.Biophysical reviews · 2026Review
- 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
- The cardiac phospho-proteome during pressure overload in mice.Scientific data · 2025Article
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Mechanisms of a novel regulatory light chain-dependent cardiac myosin inhibitor.The Journal of general physiology · 2024Article
- Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy.iScience · 2024Article
- Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.JACC. Basic to translational science · 2024Article
- Fine tuning contractility: atrial sarcomere function in health and disease.American journal of physiology. Heart and circulatory physiology · 2024Review
- Myofilament dysfunction in diastolic heart failure.Heart failure reviews · 2024Review
- Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM.Life (Basel, Switzerland) · 2023Article
- Using Multiscale Simulations as a Tool to Interpret Equatorial X-ray Fiber Diffraction Patterns from Skeletal Muscle.International journal of molecular sciences · 2023Article
- Article
- Synthetic growth hormone-releasing hormone agonist ameliorates the myocardial pathophysiology characteristic of heart failure with preserved ejection fraction.Cardiovascular research · 2023Article
- Cardiac Sarcomere Signaling in Health and Disease.International journal of molecular sciences · 2022Review
- Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.International journal of molecular sciences · 2022Article
- Titin force in muscle cells alters lattice order, thick and thin filament protein formation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart.Nature communications · 2022Article
- Small Angle X-ray Diffraction as a Tool for Structural Characterization of Muscle Disease.International journal of molecular sciences · 2022Review
- Molecular basis of force-pCa relation inProceedings of the National Academy of Sciences of the United States of America · 2022Article
2 more citing papers are in PubMed but not listed here.
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9 authors at 2 institutions in 1 country.
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Abstract
Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 → Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. We hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In support of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca(2+) sensitivity observed in D166V-mutated hearts were reversed in S15D-D166V mice. Low-angle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype.
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