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van Dijk, Sabine J.; Boontje, Nicky M.; Heymans, Martijn W.; ten Cate, Folkert J.; Michels, Michelle; dos Remedios, Cris; Dooijes, Dennis; van Slegtenhorst, Marjon A.; van der Velden, Jolanda; Stienen, Ger J. M.
Pflügers Archiv, 08/2014, Letnik: 466, Številka: 8Journal Article
Mutations in the MYBPC3 gene, encoding cardiac myosin binding protein C (cMyBP-C) are frequent causes of hypertrophic cardiomyopathy (HCM). Previously, we have presented evidence for reduced cMyBP-C expression (haploinsufficiency), in patients with a truncation mutation in MYBPC3 . In mice, lacking cMyBP-C cross-bridge kinetics was accelerated. In this study, we investigated whether cross-bridge kinetics was altered in myectomy samples from HCM patients harboring heterozygous MYBPC3 mutations (MYBPC3 mut ). Isometric force and the rate of force redevelopment ( k tr ) at different activating Ca 2+ concentrations were measured in mechanically isolated Triton-permeabilized cardiomyocytes from MYBPC3 mut ( n = 18) and donor ( n = 7) tissue. Furthermore, the stretch activation response of cardiomyocytes was measured in tissue from eight MYBPC3 mut patients and five donors to assess the rate of initial force relaxation ( k 1 ) and the rate and magnitude of the transient increase in force ( k 2 and P 3 , respectively) after a rapid stretch. Maximal force development of the cardiomyocytes was reduced in MYBPC3 mut (24.5 ± 2.3 kN/m 2 ) compared to donor (34.9 ± 1.6 kN/m 2 ). The rates of force redevelopment in MYBPC3 mut and donor over a range of Ca 2+ concentrations were similar ( k tr at maximal activation: 0.63 ± 0.03 and 0.75 ± 0.09 s −1 , respectively). Moreover, the stretch activation parameters did not differ significantly between MYBPC3 mut and donor ( k 1 : 8.5±0.5 and 8.8 ± 0.4 s −1 ; k 2 : 0.77 ± 0.06 and 0.74 ± 0.09 s −1 ; P 3 : 0.08 ± 0.01 and 0.09 ± 0.01, respectively). Incubation with protein kinase A accelerated k 1 in MYBPC3 mut and donor to a similar extent. Our experiments indicate that, at the cMyBP-C expression levels in this patient group (63 ± 6 % relative to donors), cross-bridge kinetics are preserved and that the depressed maximal force development is not explained by perturbation of cross-bridge kinetics.
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