ArticleThe Journal of general physiology2023
Single-molecule imaging reveals how mavacamten and PKA modulate ATP turnover in skeletal muscle myofibrils.
Article in The Journal of general physiology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 27 citations in OpenAlex.
- Kinetic modeling of mant-ATP turnover to interpret the biochemically defined myosin SRX state.Biophysical journal · 2026Article
- Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy.eLife · 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
- The thin line between biochemistry and structure where myosin super relaxed state lies.Biophysical reviews · 2026Review
- Hypertrophic Cardiomyopathy is a Disease of Sarcomere Proteins.Methodist DeBakey cardiovascular journal · 2026Review
- Direct measurement of mavacamten and deoxyATP perturbation of the SRX/DRX ratio in porcine cardiac myofibrils using a simple, accessible and multiplexed approach.Journal of muscle research and cell motility · 2025Article
- Resolving zone-specific regulation of cardiac myosin.The Journal of general physiology · 2025Article
- Mavacamten facilitates myosin head ON-to-OFF transitions and shortens thin filament length in relaxed mouse skeletal muscle.Physiological reports · 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
- CaJournal of molecular and cellular cardiology · 2025Article
- Probing actin-activated ATP turnover kinetics of human cardiac myosin II by single molecule fluorescence.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Interacting myosin head dynamics and their modification by 2'-deoxy-ADP.Biophysical journal · 2024Article
- Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy.The EMBO journal · 2024Review
- Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads.Nature communications · 2024Article
- Myosins may know when to hold and when to fold.Biophysical journal · 2024Article
- Myosin-binding protein C forms C-links and stabilizes OFF states of myosin.bioRxiv : the preprint server for biology · 2023Article
- Super relaxed myosins loosen up to different cues in cardiac and skeletal muscle sarcomeres.The Journal of general physiology · 2023Article
- Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies.American journal of physiology. Cell physiology · 2023Review
- Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle.The Journal of general physiology · 2023Article
- Comparing the efficacy and safety of medications in adults with hypertrophic cardiomyopathy: a systematic review and network meta-analysis.Frontiers in cardiovascular medicine · 2023Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Muscle contraction is controlled at two levels: the thin and the thick filaments. The latter level of control involves three states of myosin heads: active, disordered relaxed (DRX), and super-relaxed (SRX), the distribution of which controls the number of myosins available to interact with actin. How these are controlled is still uncertain. Using fluorescently labeled ATP, we were able to spatially assign the activity of individual myosins within the sarcomere. We observed that SRX comprises 53% of all heads in the C-zone compared with 35% and 44% in the P- and D-zones, respectively. The recently FDA-approved hypertrophic cardiomyopathy drug, mavacamten (mava), significantly decreased DRX, favoring SRX in both the C- and D-zones at 60% and 63%, respectively. Since thick filament regulation is in part regulated by the myosin-binding protein-C (MyBP-C), we also studied PKA phosphorylation. This had the opposite effect as mava, specifically in the C-zone where it decreased SRX to 34%, favoring DRX. These results directly show that excess concentrations of mava do increase SRX, but the effect is limited across the sarcomere, suggesting mava is less effective on skeletal muscle. In addition, we show that PKA directly affects the contractile machinery of skeletal muscle leading to the liberation of repressed heads. Since the effect is focused on the C-zone, this suggests it is likely through MyBP-C phosphorylation, although our data suggest that a further reserve of myosins remain that are not accessible to PKA treatment.
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