Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations

SJ van Dijk, NM Boontje, MW Heymans, Folkert ten Cate, Michelle Michels, C dos Remedios, D Dooijes, Marjon van Slegtenhorst, J Velden, GJM Stienen

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Abstract

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 Ca2+ 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 Ca2+ 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.
Original languageUndefined/Unknown
Pages (from-to)1619-1633
Number of pages15
JournalPflugers Archiv-European Journal of Physiology
Volume466
Issue number8
DOIs
Publication statusPublished - 2014

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