Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin

Abstract

The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM), normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation, enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in patients with DCM, whereas inhibiting myosin by MYK-461 should benefit the substantial proportion of patients with HCM with MYBPC3 mutations.

The molecular basis of hypercontractility caused by the hypertrophic cardiomyopathy mutations R403Q and R663H

“…The potential importance of a folded-back sequestered state of cardiac myosin has recently been highlighted in diseases like HCM, and also in the mechanism of action of cardiac inhibitors like mavacamten (15,37,38). The cardiac activator omecamtiv mecarbil has also been shown to stabilize the open state of cardiac myosin while also impacting the kinetics of actin-bound myosin motors (39)(40)(41).…”

Hypertrophic cardiomyopathy: the future of treatment

“…Myosin contains the ATPase involved in actin–myosin cross bridging and muscle fibre shortening – in this way serving as the molecular motor for myocardial contraction. Mutations in MYH7 are known to affect the activity of myosin ATPase and increase myocardial force generation, while MYBPC plays a role in sarcomere organization and may serve as a brake on myofibril contraction . It is hypothesized that HCM mutations increase net power generation by the sarcomere resulting in LV hypercontractility and stiffening that is clinically observed.…”

“…Mutations in MYH7 are known to affect the activity of myosin ATPase and increase myocardial force generation, while MYBPC plays a role in sarcomere organization and may serve as a brake on myofibril contraction. 30,31 It is hypothesized that HCM mutations increase net power generation by the sarcomere resulting in LV hypercontractility and stiffening that is clinically observed. Mavacamten (MyoKardia, Inc., South San Francisco, CA, USA), a first-in-class oral small molecule, targets this process directly as an allosteric modulator of cardiac -myosin, causing reversible inhibition of actin-myosin cross bridging.…”

Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

“…They also question the physiological relevance of at least some murine models which are known to have striking species differences relative to humans [52]. In others, such as mouse and human muscle fibers bearing the F764L-MYBPC3 HCM mutation, a hypercontractile phenotype was consistently reported in both [90]. Notwithstanding, whole-organism in vivo models do not simply reflect situations in vitro.…”