The myosin-activated thin filament regulatory state, M − -open: a link to hypertrophic cardiomyopathy (HCM)

This review proposes a link between the hypertrophic (HCM) and restrictive cardiomyopathies caused by mutations in several sarcomeric thin filament proteins, and the open state of the three-state muscle regulation theory. The three characteristics of various muscle systems reconstituted from HCM mutated proteins (increased Ca2+-sensitivity, increased basal activity in the absence of Ca2+, and decreased cooperativity) can be explained by the contribution of a myosin-induced open state (M − ), which elevates the basal activity and competes with the normal Ca2+-activated pathway. A model based on the three-state theory of regulation, shows how a change in the closed/blocked equilibrium caused by a mutation that weakens the binding of troponin I to tropomyosin-actin can produce the characteristics of HCM. This review also shows that in the M − state, Ca2+ can shift the closed–open equilibrium of the N-terminal hydrophobic region of troponin C without affecting activity.