Myosin in autoinhibited <i>off</i> state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions.

ABSTRACT: 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 off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca²⁺, 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 Ca²⁺ increases myosin ATPase activity b

SUBMITTER: Ma W 

PROVIDER: S-EPMC10895252 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature