Myosin Modulator Aficamten Inhibits Force by Altering Myosin’s Biochemical Activity Without Changing Thick Filament Structure
We investigated the effects of aficamten on cardiac muscle structure, biochemical activity, and contractile function. Aficamten does not structurally sequester myosin heads along the thick filament. It inhibits ATPase activity by decreasing myosin ATPase cycling kinetics, with the emergence of a super slow biochemical nucleotide turnover. This results in decreased force and calcium sensitivity without altering cross-bridge cycling. Our myofibril mechanical assay showed inhibition of force with accelerated relaxation. In engineered heart tissues, while mavacamten and aficamten inhibit cardiac twitch forces, mavacamten reduces the activation kinetics while both accelerate relaxation.
Authors
- Bertrand C.W. Tanner (ORCID: https://orcid.org/0000-0003-1711-8526)
- Max Mahoney-Schaefer
- Kyrah L. Turner (ORCID: https://orcid.org/0000-0001-8653-1256)
- Thomas C. Irving (ORCID: https://orcid.org/0000-0003-4848-3323)
- Christian Mandrycky (ORCID: https://orcid.org/0000-0002-6564-7265)
- Weikang Ma (ORCID: https://orcid.org/0000-0001-9535-7114)
- Jing Zhao (ORCID: https://orcid.org/0000-0001-5177-5699)
- Farid Moussavi‐Harami (ORCID: https://orcid.org/0000-0002-0189-7214)
- Anthony Asencio (ORCID: https://orcid.org/0000-0002-8147-0180)
- Kristina B. Kooiker (ORCID: https://orcid.org/0000-0003-1817-9080)
- Timothy S. McMillen (ORCID: https://orcid.org/0000-0001-5261-3229)
- Galina Flint (ORCID: https://orcid.org/0000-0003-3993-5156)
- Neil M. Kad (ORCID: https://orcid.org/0000-0002-3491-8595)
- Michael Regnier (ORCID: https://orcid.org/0000-0001-5437-9851)
- Matvey Pilagov (ORCID: https://orcid.org/0000-0002-1915-382X)
- Saffie Mohran (ORCID: https://orcid.org/0000-0003-0728-9882)
- Ateeqa Naim
- Siyao Jiang
Institutions
- Illinois Institute of Technology (US)
- Dalian Medical University (CN)
- University of Washington (US)
- University of Kent (GB)
- University of Washington Applied Physics Laboratory (US)
Publication Details
- Journal
- JACC Basic to Translational Science
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1016/j.jacbts.2025.101449
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00