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Single-molecule imaging reveals how mavacamten and PKA modulate ATP turnover in skeletal muscle myofibrils

Pilagov, Matvey, Heling, Laurens W.H.J., Walklate, Jonathan, Geeves, Michael A., Kad, Neil M. (2022) Single-molecule imaging reveals how mavacamten and PKA modulate ATP turnover in skeletal muscle myofibrils. Journal of General Physiology, 155 (1). Article Number e202213087. ISSN 0022-1295. E-ISSN 1540-7748. (doi:10.1085/jgp.202213087) (KAR id:98349)

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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.

Item Type: Article
DOI/Identification number: 10.1085/jgp.202213087
Uncontrolled keywords: Myosins - chemistry, Single Molecule Imaging, Myofibrils, Muscle, Skeletal - physiology, Adenosine Triphosphate
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: University of Kent (
European Union (
SWORD Depositor: JISC Publications Router
Depositing User: JISC Publications Router
Date Deposited: 05 Dec 2022 16:26 UTC
Last Modified: 17 Feb 2023 15:30 UTC
Resource URI: (The current URI for this page, for reference purposes)
Pilagov, Matvey:
Heling, Laurens W.H.J.:
Walklate, Jonathan:
Geeves, Michael A.:
Kad, Neil M.:
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