Key result
The R712L mutation in beta-cardiac myosin decreases the working stroke amplitude 4-fold, an impairment that is reversibly rescued by the heart failure drug omecamtiv mecarbil.
Why the study?
Over 300 mutations across β-cardiac myosin cause HCM, including the motor mutation R712L which leads to severe HCM, but the mechanism underlying its effects and response to omecamtiv mecarbil was unclear.
The R712L mutation uncouples lever arm rotation from ATPase activity, challenging the hypothesis that all HCM mutants are hypercontractile, and this defect can be rescued by omecamtiv mecarbil.
Challenges HCM hypercontractility assumption in this model; leaves open whether omecamtiv mecarbil rescue translates to patients.
Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.
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Snoberger et al. (2020) studied Hypertrophic cardiomyopathy. Omecamtiv mecarbil vs. Untreated R712L-myosin was evaluated on Working stroke amplitude. The R712L mutation in beta-cardiac myosin decreases the working stroke amplitude 4-fold, an impairment that is reversibly rescued by the heart failure drug omecamtiv mecarbil.
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