Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse α-cardiac myosin in the laser trap assay

Point mutations in cardiac myosin, the heart's molecular motor, produce distinct clinical phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Do mutations alter myosin's molecular mechanics in a manner that is predictive of the clinical outcome? We have directly characterized the maximal force-generating capacity (Fmax) of two HCM (R403Q, R453C) and two DCM (S532P, F764L) mutant myosins isolated from homozygous mouse models using a novel load-clamped laser trap assay. Fmax was 50% (R403Q) and 80% (R453C) greater for the HCM mutants compared with the wild type, whereas Fmax was severely depressed for one of the DCM mutants (65% S532P). Although Fmax was normal for the F764L DCM mutant, its actin-activated ATPase activity and actin filament velocity (Vactin) in a motility assay were significantly reduced (Schmitt JP, Debold EP, Ahmad F, Armstrong A, Frederico A, Conner DA, Mende U, Lohse MJ, Warshaw D, Seidman CE, Seidman JG. Proc Natl Acad Sci USA 103: 14525–14530, 2006.). These Fmax data comb...