Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-02, Vol.121 (8), p.e2314914121
• Main Authors: Ma, Weikang, Del Rio, Carlos L, Qi, Lin, Prodanovic, Momcilo, Mijailovich, Srboljub, Zambataro, Christopher, Gong, Henry, Shimkunas, Rafael, Gollapudi, Sampath, Nag, Suman, Irving, Thomas C
• Format: Article
• Language: English
• Subjects: Animals; BASIC BIOLOGICAL SCIENCES; Benzylamines - pharmacology; Biological Sciences; Calcium; Calcium ions; Cardiac output; Cardiomyocytes; Enzymatic activity; Filaments; Heart rate; Muscle Contraction; Myocytes, Cardiac; Myosin; Myosin ATPase; Myosins; Physiology; Rats; Science & Technology - Other Topics; Stimulation; Stroke volume; Uracil - analogs & derivatives; Ventricle
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2314914121

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered states close to the thick filament backbone. It remains elusive whether these myosin heads in the state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these state(s) by mavacamten are recruitable by 1) Ca , 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca and passive lengthening can shift mavacamten-ordered myosin heads from positions close to the thick filament backbone to disordered states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dt an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.