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J Physiol. 2014 Aug 1;592(15):3257-72. doi: 10.1113/jphysiol.2014.274571. Epub 2014 Jun 13.

Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation.

Author information

1
Department of Physiology, VU University Medical Centre, Amsterdam, The Netherlands e.paalberends@vumc.nl.
2
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
3
Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.
4
Department of Physiology, VU University Medical Centre, Amsterdam, The Netherlands Department of Physics and Astronomy, VU University, Amsterdam, The Netherlands.
5
Thorax Centre, Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
6
Brigham and Women's Hospital, Cardiology, Boston, USA.
7
Department of Physiology, VU University Medical Centre, Amsterdam, The Netherlands ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.

Abstract

The first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain (β-MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross-bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross-bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation-negative HCM patients (HCMsmn). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCMsmn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s(-1), respectively). Moreover, compared to HCMsmn, tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l(-1) s(-1) kN(-1) m(-2), respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross-bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn. Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation.

PMID:
24928957
PMCID:
PMC4146374
DOI:
10.1113/jphysiol.2014.274571
[Indexed for MEDLINE]
Free PMC Article

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