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Published on: August 8, 2022
Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations
Sabine J van Dijk1, Nicky M Boontje, Martijn W Heymans
1Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
Insights
Mutations in the MYBPC3 gene cause hypertrophic cardiomyopathy (HCM). This study found that while cardiac myosin binding protein C (cMyBP-C) levels were reduced in HCM patients, their muscle cross-bridge kinetics remained preserved, indicating other mechanisms contribute to depressed force development.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Genetic Cardiology
Background:
- Mutations in the MYBPC3 gene are a common cause of hypertrophic cardiomyopathy (HCM).
- Previous studies suggest reduced cardiac myosin binding protein C (cMyBP-C) expression (haploinsufficiency) and accelerated cross-bridge kinetics in mouse models.
- The precise impact of MYBPC3 mutations on cardiomyocyte mechanics in human HCM patients remains incompletely understood.
Purpose of the Study:
- To investigate whether cross-bridge kinetics are altered in cardiomyocytes from HCM patients with heterozygous MYBPC3 mutations.
- To determine if reduced cMyBP-C expression in HCM patients affects force generation and kinetic properties.
- To elucidate the mechanistic link between MYBPC3 mutations, cMyBP-C levels, and cardiac dysfunction.
Main Methods:
- Mechanically isolated Triton-permeabilized cardiomyocytes were obtained from myectomy samples of HCM patients (MYBPC3mut, n=18) and donor controls (n=7).
- Isometric force and the rate of force redevelopment (k tr) were measured at varying calcium (Ca2+) concentrations.
- Stretch activation response, including rates of force relaxation (k 1) and transient force increase (k 2, P 3), was assessed.
Main Results:
- Maximal force development was significantly reduced in MYBPC3mut cardiomyocytes compared to donor controls (24.5 vs. 34.9 kN/m2).
- The rates of force redevelopment (k tr) and stretch activation parameters (k 1, k 2, P 3) were similar between MYBPC3mut and donor groups.
- Protein kinase A treatment similarly accelerated k 1 in both groups, suggesting preserved regulatory pathways.
Conclusions:
- Despite reduced cMyBP-C expression (approximately 63% of donor levels), cardiomyocyte cross-bridge kinetics are preserved in HCM patients with MYBPC3 mutations.
- The depressed maximal force development observed in these patients is not attributable to alterations in cross-bridge kinetics.
- These findings highlight that other molecular or structural changes likely underlie the force deficit in MYBPC3-related HCM.
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 (MYBPC3mut). 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 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/m(2)) compared to donor (34.9 ± 1.6 kN/m(2)). The rates of force redevelopment in MYBPC3mut 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 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.
