title: Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation.
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.
authors.affiliation: Department of Physiology, VU University Medical Centre, Amsterdam, The Netherlands e.paalberends@vumc.nl.
authors.forename: E Rosalie
authors.initials: ER
authors.lastname: Witjas-Paalberends
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferrara
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Scellini
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Piroddi
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Montag
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesi
authors.affiliation: Department of Physiology, VU University Medical Centre, Amsterdam, The Netherlands Department of Physics and Astronomy, VU University, Amsterdam, The Netherlands.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: Thorax Centre, Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Michels
authors.affiliation: Brigham and Women's Hospital, Cardiology, Boston, USA.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Poggesi
authors.affiliation: Department of Physiology, VU University Medical Centre, Amsterdam, The Netherlands ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation; D020125:Mutation, Missense; D009200:Myocardial Contraction; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism / Q000502:physiology*
chemical_list: C501641:MYH7 protein, human; D000255:Adenosine Triphosphate; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains