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Abstract <p>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 <i>MYBPC3</i> gene encoding cardiac myosin-binding protein&#xa0;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 <i>in&#xa0;vitro</i> motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in the <i>in&#xa0;vitro</i> 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.</p>

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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

  • 期刊论文

  • 发表日期：

    2025年3月1日

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  • Anastasia M. Kochurova,
  • Evgenia A. Beldiia,
  • Julia Y. Antonets,
  • Victoria V. Nefedova,
  • Natalia S. Ryabkova,
  • Ivan A. Katrukha,
  • Sergey Y. Bershitsky,
  • Alexander M. Matyushenko,
  • Galina V. Kopylova,
  • Daniil V. Shchepkin

摘要

Abstract

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.