ISOMETRIC TENSION AND MUTANT MYOSIN HEAVY-CHAIN CONTENT IN SINGLE SKELETAL MYOFIBERS FROM HYPERTROPHIC CARDIOMYOPATHY PATIENTS

Several mutations in the beta-myosin heavy chain (beta-MHC) gene have been linked to hypertrophic cardiomyopathy (HCM). Because this gene is also expressed in slow-twitch fibers of skeletal muscle, we have been able to study the mutant beta-myosin content and mechanical propertie s associated with these myosin mutations in single skinned skeletal mu scle fibers obtained from HCM patients. We found that in patients carr ying the 403(Arg-->Gla) mutation, the mutant beta-MHC comprises 47.3 /- 9.1% of the total beta-MHC present in single slow-twitch fibers. Th erefore, both alleles of the beta-MHC gene are on average equally expr essed. Isometric tension was decreased by 18% in slow fibers from HCM patients with the 403(Arg-->Gla) mutation, but was unchanged in slow f ibers from patients with two other beta-MHC gene mutations. Taken toge ther with the previous demonstration of reduced velocities generated b y these myosins in an in vitro assay, our results suggest that the mut ant beta-myosins are functional molecular meters that are able to gene rate tension and movement, but with abnormal kinetics. (C) 1997 Academ ic Press Limited.