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 properties associated with these myosin mutations in single skinned skeletal muscle fibers obtained from HCM patients. We found that in patients carrying the 403Arg-->Gln mutation, the mutant beta-MHC comprises 47.3 +/- 9.1% of the total beta-MHC present in single slow-twitch fibers. Therefore, both alleles of the beta-MHC gene are on average equally expressed. Isometric tension was decreased by 18% in slow fibers from HCM patients with the 403Arg-->Gln mutation, but was unchanged in slow fibers from patients with two other beta-MHC gene mutations. Taken together with the previous demonstration of reduced velocities generated by these myosins in an in vitro assay, our results suggest that the mutant beta-myosins are functional molecular motors that are able to generate tension and movement, but with abnormal kinetics.
Malinchik
S
S
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cuda
G
G
Podolsky
R J
RJ
Horowits
R
R
D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D006801:Humans; D007537:Isometric Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000737:chemistry*; D018657:Muscle Fibers, Slow-Twitch / Q000737:chemistry / Q000502:physiology; D018482:Muscle, Skeletal / Q000737:chemistry*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*
D018995:Myosin Heavy Chains; D002118:Calcium