ArticlePNAS nexus2024
The structural OFF and ON states of myosin can be decoupled from the biochemical super- and disordered-relaxed states.
Article in PNAS nexus, 2024. 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, 39 citations in OpenAlex.
- Diastolic contributors in cardiomyocytes of a cardiometabolic HFpEF-like mouse model.The Journal of general physiology · 2026Article
- Mechanistic diversity within RLC-dependent myosin ATPase inhibitors differentiates EDG-7500, a diastolic-selective cardiac sarcomere modulator.JCI insight · 2026Article
- Kinetic modeling of mant-ATP turnover to interpret the biochemically defined myosin SRX state.Biophysical journal · 2026Article
- Piperine disrupts the OFF state of the resting thick filament of rat skeletal muscle, enhancing dynamic contractility in a fibre-type-dependent manner.The Journal of physiology · 2026Article
- Myosin motor dynamics and cardiac function: Insights from in vivo small-angle X-ray scattering and pressure-volume analysis.The Journal of physiology · 2026Article
- Mavacamten shows broad benefit in human and mouse models of MYBPC3-related hypertrophic cardiomyopathy.Nature cardiovascular research · 2026Article
- Subsarcomeric regulation of thin and thick filaments in skeletal muscle myofibrils.Proceedings of the National Academy of Sciences of the United States of America · 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
- The thin line between biochemistry and structure where myosin super relaxed state lies.Biophysical reviews · 2026Review
- Modulating the myosin super-relaxed state as a therapeutic strategy for myosin light chain-linked cardiomyopathies.Biophysical reviews · 2026Review
- Changes in cardiac myosin acetylation disrupt the super-relaxed state in genotype-negative hypertrophic cardiomyopathy with type 2 diabetes.Cardiovascular diabetology · 2026Article
- Porcine Left Atrial and Ventricular Thick Filaments Exhibit Distinct Resting Structures and Calcium-dependent Responses.bioRxiv : the preprint server for biology · 2026Article
- Cryo-EM reveals how cardiomyopathy therapeutic drugs modulate the myosin motors of the heart.Science advances · 2026Article
- A primer on the methods of skeletal and cardiac muscle mechanics using permeabilized preparations.The Journal of general physiology · 2026Review
- Mitochondrial Impairment in Unloaded Postural Muscle: Mechanisms Driving Loss of Muscle Function and Mass.Antioxidants (Basel, Switzerland) · 2026Review
- Destabilization of cardiac myosin acetylation and sequestration with type 2 diabetes mellitus.Cardiovascular diabetology · 2026Article
- A new era of understanding of the control of thick filament states in the heartbeat.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Hypertrophic cardiomyopathy mutations Y115H and E497D disrupt the folded-back state of human β-cardiac myosin allosterically.Nature communications · 2025Article
- Heterogeneous Dysregulation of Myosin Super-Relaxation and Energetics in Hypertrophic Cardiomyopathy.Circulation. Heart failure · 2025Article
- A FRET assay to monitor different structural states of human β-cardiac myosin including the interacting-heads motif.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
There is a growing awareness that both thick-filament and classical thin-filament regulations play central roles in modulating muscle contraction. Myosin ATPase assays have demonstrated that under relaxed conditions, myosin may reside either in a high-energy-consuming disordered-relaxed (DRX) state available for binding actin to generate force or in an energy-sparing super-relaxed (SRX) state unavailable for actin binding. X-ray diffraction studies have shown that the majority of myosin heads are in a quasi-helically ordered OFF state in a resting muscle and that this helical ordering is lost when myosin heads are turned ON for contraction. It has been assumed that myosin heads in SRX and DRX states are equivalent to the OFF and ON states, respectively, and the terms have been used interchangeably. In this study, we use X-ray diffraction and ATP turnover assays to track the structural and biochemical transitions of myosin heads, respectively, induced with either omecamtiv mecarbil (OM) or piperine in relaxed porcine myocardium. We find that while OM and piperine induce dramatic shifts of myosin heads from the OFF to the ON state, there are no appreciable changes in the population of myosin heads in the SRX and DRX states in both unloaded and loaded preparations. Our results show that biochemically defined SRX and DRX can be decoupled from structurally defined OFF and ON states. In summary, while SRX/DRX and OFF/ON transitions can be correlated in some cases, these two phenomena are measured using different approaches, reflect different properties of the thick filament, and should be investigated and interpreted separately.
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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.