Mavacamten Inhibits the Effect of the N-Terminal Fragment of Cardiac Myosin-Binding Protein C with the L352P Mutation on the Actin–Myosin Interaction at Low Calcium Concentrations

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Anastasia M. Kochurova¹, Evgenia A. Beldiia¹, Julia Y. Antonets¹, Victoria V. Nefedova², Natalia S. Ryabkova^3,4, Ivan A. Katrukha^3,4, Sergey Y. Bershitsky¹, Alexander M. Matyushenko², Galina V. Kopylova¹, Daniil V. Shchepkin^1,a*

¹Institute of Immunology and Physiology, Russian Academy of Sciences, 620049 Yekaterinburg, Russia

²Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia

³Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia

⁴Hytest Ltd., Turku, 20520, Finland

^* To whom correspondence should be addressed.

Received: November 19, 2024; Revised: March 13, 2025; Accepted: March 13, 2025

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Hypertrophic cardiomyopathy (HCM)-associated mutations in sarcomeric proteins lead to the disruption of the actin–myosin interaction and its calcium regulation and cause myocardial hypercontractility. About half of such mutations are found in the MYBPC3 gene encoding cardiac myosin-binding protein C (cMyBP-C). A new approach to normalize cardiac contractile function in HCM is the use of β-cardiac myosin function inhibitors, one of which is mavacamten. We studied the effect of mavacamten on the calcium regulation of the actin–myosin interaction using isolated cardiac contractile proteins in the in vitro motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in the in vitro motility assay and the calcium sensitivity of the velocity but led to the underinhibition of the actin–myosin interaction at low calcium concentrations. Mavacamten decreased the maximum sliding velocity of thin filaments in the presence of the WT and L352P C0-C2 fragments, and abolished their movement in the presence of the L352P C0-C2 fragment at low calcium concentrations. Slowing down the kinetics of cross-bridges and inhibition of actin–myosin interaction at low calcium concentrations by mavacamten may reduce the hypercontractility in HCM and the degree of myocardial hypertrophy.

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KEY WORDS: actin–myosin interaction, hypertrophic cardiomyopathy, mavacamten, calcium regulation, in vitro motility assay, cardiac myosin-binding protein C

DOI: 10.1134/S0006297924604131

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