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 (MYBPC3mut). Isometric force and the rate of force redevelopment (ktr) at different activating Ca2+ concentrations were measured in mechanically isolated Triton-permeabilized cardiomyocytes from MYBPC3mut (n = 18) and donor (n = 7) tissue. Furthermore, the stretch activation response of cardiomyocytes was measured in tissue from eight MYBPC3mut patients and five donors to assess the rate of initial force relaxation (k1) and the rate and magnitude of the transient increase in force (k2 and P3, respectively) after a rapid stretch. Maximal force development of the cardiomyocytes was reduced in MYBPC3mut (24.5 ± 2.3 kN/m2) compared to donor (34.9 ± 1.6 kN/m2). The rates of force redevelopment in MYBPC3mut and donor over a range of Ca2+ concentrations were similar (ktr 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 MYBPC3mut and donor (k1: 8.5±0.5 and 8.8 ± 0.4 s-1; k2: 0.77 ± 0.06 and 0.74 ± 0.09 s-1; P3: 0.08 ± 0.01 and 0.09 ± 0.01, respectively). Incubation with protein kinase A accelerated k1 in MYBPC3mut 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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doi.org/10.1007/s00424-013-1391-0, hdl.handle.net/1765/68223
Pfluegers Archiv: European journal of physiology
Department of Clinical Genetics

van Dijk, S.J, Boontje, N.M, Heymans, M.W, ten Cate, F.J, Michels, M, dos Remedios, C, … Stienen, G.J.M. (2013). Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations. Pfluegers Archiv: European journal of physiology, 1–15. doi:10.1007/s00424-013-1391-0