Modeling mechanisms of the thick-filament off-state dynamics in cardiac muscle.

Abstract

Cardiac muscle contraction is initiated when sarcomeric thin filaments are activated by a cytosolic Ca2+ transient. Experimental evidence suggests that the contraction strength is modulated by an additional thick-filament activation. Myosin heads in the so-called OFF state are blocked from interacting with thin filaments and therefore cannot produce force. Transitions to the ON state liberate myosin heads, making them available for producing force. Evidence suggests that this transition is itself tension-dependent, but the precise nature and mechanism of this mechanosensitivity remain unclear. The relevance and contribution of passive tension (titin strain) are indicated by some experiments but refuted by others. Furthermore, tension is unlikely to be uniform within the thick filament, which makes the detailed characterization of the mechanosensitivity ambiguous. The precise representation of the mechanosensitivity may have significant repercussions at the tissue and anatomical levels, and hence on cardiac function.