Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations
Autor: | Sabine J. van Dijk, Michelle Michels, Folkert J. ten Cate, Dennis Dooijes, Cris dos Remedios, Ger J.M. Stienen, Marjon van Slegtenhorst, Jolanda van der Velden, Nicky M. Boontje, Martijn W. Heymans |
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Přispěvatelé: | Cardiology, Clinical Genetics, Physiology, Epidemiology and Data Science, ICaR - Heartfailure and pulmonary arterial hypertension, Methodology and Applied Biostatistics, Physics of Living Systems |
Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
Adult
Male Physiology Clinical Biochemistry Kinetics Isometric exercise Young Adult SDG 3 - Good Health and Well-being Physiology (medical) medicine Humans Myocytes Cardiac Protein kinase A Receptor Aged Chemistry Hypertrophic cardiomyopathy Cardiac muscle Anatomy Cardiomyopathy Hypertrophic Middle Aged medicine.disease Myocardial Contraction Molecular biology medicine.anatomical_structure Mutation cardiovascular system Female medicine.symptom Carrier Proteins Haploinsufficiency Muscle contraction |
Zdroj: | van Dijk, S J, Boontje, N M, Heymans, M W, ten Cate, F J, Michels, M, dos Remedios, C, Dooijes, D, van Slegtenhorst, M A, van der Velden, J & Stienen, G J M 2014, ' Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations ', Pflügers Archiv European Journal of Physiology, vol. 466, no. 8, pp. 1619-1633 . https://doi.org/10.1007/s00424-013-1391-0 Pflugers Archiv-European Journal of Physiology, 466(8), 1619-1633. Springer-Verlag Pflügers Archiv European Journal of Physiology, 466(8), 1619-1633. Springer Verlag |
ISSN: | 0031-6768 |
DOI: | 10.1007/s00424-013-1391-0 |
Popis: | 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 (k tr) 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 (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 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 (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 MYBPC3mut 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 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. |
Databáze: | OpenAIRE |
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