Cardiac myosin filaments are directly regulated by calcium

Abstract

Contraction of cardiac and skeletal muscle is initiated by calcium (Ca²⁺) binding to regulatory proteins on actin-containing thin filaments. During muscle contraction, structural changes in Ca²⁺-dependent thin filament allow the binding of myosin motors to drive muscle contraction¹. The dynamic switching between the resting off states and the active on states of myosin is also critical in regulating muscle contractility^2–4. However, the molecular switch on the myosin-containing thick filament that drives this process is not understood. Here we show that cardiac thick filaments are directly Ca²⁺-regulated. We find that Ca²⁺ progressively moves the myosin heads from ordered off states close to the thick filament backbone to disordered on states closer to the thin filaments. This Ca²⁺-dependent structural shift of myosin is accompanied by a biochemically defined transition from the inactive super-relaxed state(s) to the active disordered relaxed state(s)³. Furthermore, we find that this Ca²⁺-mediated molecular switching is an intrinsic property of cardiac myosin but only when assembled into thick filaments. This novel concept of Ca²⁺ as a regulatory modulator of the thick filament provides a fresh perspective on cardiac muscle regulation, which may be particularly valuable for devising restorative treatments for pathologies altering the Ca²⁺ sensitivity of the sarcomere.