Abnormal contractile properties of muscle fibers expressing β-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy

Missense mutations in the β-myosin heavy chain (β-MHC) gene cause hypertrophic cardiomyopathy (HCM). As normal and mutant β-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct β-MHC gene mutations and normal controls. Fibers with the 741(Gly→Arg) mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal). Fibers with the 403(Arg→Gln) mutation (at the actin interface of myosin) showed lowered force/stiffness ratio (56% of normal) and depressed velocity of shortening (50% of normal). Both the 741(Gly→Arg) and 403(Arg→Gln) mutation-containing fibers displayed abnormal force-velocity relationships and reduced power output. Fibers with the 256(Gly→Glu) mutation (end of ATP-binding pocket) had contractile properties that were indistinguishable from normal. Thus there is variability in the nature and extent of functional impairments in skeletal fibers containing different β-MHC gene mutations, which may correlate with the severity and penetrance of the disease that results from each mutation. These functional alterations likely constitute the primary stimulus for the cardiac hypertrophy that is characteristic of this disease.