ArticleProceedings of the National Academy of Sciences of the United States of America2019
Cardiac myosin binding protein-C phosphorylation regulates the super-relaxed state of myosin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 106 citations in OpenAlex.
- Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure.Basic research in cardiology · 2026Article
- Biomechanical stress unmasks a fibroblast-dependent hypercontractile-disarray phenotype in MYBPC3 truncation HCM.APL bioengineering · 2026Article
- Immature and mature myocardium in the pathophysiology of hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2026Review
- Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy.eLife · 2026Article
- Severe obesity in human HFpEF alters contractile protein function and organization.Science (New York, N.Y.) · 2026Article
- Assaying the myosin super-relaxed state across muscle types, cells and proteins for understanding muscle biology and use in drug discovery.Nature protocols · 2026Review
- Swimming is superior to running in inducing physiological cardiac hypertrophy and enhancing myocardial performance.Scientific reports · 2026Article
- Hypertrophic Cardiomyopathy is a Disease of Sarcomere Proteins.Methodist DeBakey cardiovascular journal · 2026Review
- Myosin-binding protein C slows cardiac myofibril relaxation kinetics.The Journal of physiology · 2025Article
- Spatially resolving how cMyBP-C phosphorylation and haploinsufficiency in porcine and human myofibrils affect β-cardiac myosin activity.The Journal of general physiology · 2025Article
- Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging.JCI insight · 2025Article
- Myocardium From Patients With ATTR Amyloidosis Produces Less Force Secondary to Increased Fibrosis.JACC. Basic to translational science · 2025Article
- Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS.Cell reports methods · 2025Article
- Myosin-actin crossbridge independent sarcomere length induced CaJournal of molecular and cellular cardiology · 2025Article
- Myosin relaxation states in skeletal muscle fibers of rats and mice: Effects of sex and adiposity.Physiological reports · 2025Article
- An integrated picture of the structural pathways controlling the heart performance.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Alterations in cardiac contractile and regulatory proteins contribute to age-related cardiac dysfunction in male rats.Physiological reports · 2024Article
- Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients.Science translational medicine · 2024Article
- Abnormal phosphorylation / dephosphorylation and CaHeart failure reviews · 2024Review
- Roles of cMyBP-C phosphorylation on cardiac contractile dysfunction inJournal of molecular and cellular cardiology plus · 2024Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) accelerates cardiac contractility. However, the mechanisms by which cMyBP-C phosphorylation increases contractile kinetics have not been fully elucidated. In this study, we tested the hypothesis that phosphorylation of cMyBP-C releases myosin heads from the inhibited super-relaxed state (SRX), thereby determining the fraction of myosin available for contraction. Mice with various alanine (A) or aspartic acid (D) substitutions of the three main phosphorylatable serines of cMyBP-C (serines 273, 282, and 302) were used to address the association between cMyBP-C phosphorylation and SRX. Single-nucleotide turnover in skinned ventricular preparations demonstrated that phosphomimetic cMyBP-C destabilized SRX, whereas phospho-ablated cMyBP-C had a stabilizing effect on SRX. Strikingly, phosphorylation at serine 282 site was found to play a critical role in regulating the SRX. Treatment of WT preparations with protein kinase A (PKA) reduced the SRX, whereas, in nonphosphorylatable cMyBP-C preparations, PKA had no detectable effect. Mice with stable SRX exhibited reduced force production. Phosphomimetic cMyBP-C with reduced SRX exhibited increased rates of tension redevelopment and reduced binding to myosin. We also used recombinant myosin subfragment-2 to disrupt the endogenous interaction between cMyBP-C and myosin and observed a significant reduction in the population of SRX myosin. This peptide also increased force generation and rate of tension redevelopment in skinned fibers. Taken together, this study demonstrates that the phosphorylation-dependent interaction between cMyBP-C and myosin is a determinant of the fraction of myosin available for contraction. Furthermore, the binding between cMyBP-C and myosin may be targeted to improve contractile function.
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