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J Physiol Volume 586, Number 15, 3639-3644, August 1, 2008 DOI: 10.1113/jphysiol.2008.155952
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RAPID REPORT

The familial hypertrophic cardiomyopathy-associated myosin mutation R403Q accelerates tension generation and relaxation of human cardiac myofibrils

 Alexandra Belus1,2, Nicoletta Piroddi1,2, Beatrice Scellini1,2, Chiara Tesi1,2, Giulia D Amati3, Francesca Girolami4, Magdi Yacoub5,6, Franco Cecchi5,6, Iacopo Olivotto6 and Corrado Poggesi1,2

1 Department of Physiology, University of Florence, Florence, Italy
2 Center of Molecular Medicine (CIMMBA), Florence, Italy
3 Department of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy
4 Department of Genetic Diagnosis, Careggi University Hospital, Florence, Italy
5 Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy
6 Regional Referral Center for Myocardial Diseases, Careggi University Hospital, Florence, Italy

The R403Q mutation in β-myosin heavy chain was the first mutation to be identified as responsible for familial hypertrophic cardiomyopathy (FHC). In spite of extensive work on the functional sequelae of this mutation, the mechanism by which the mutant protein causes the disease has not been definitely identified. Here we directly compare contraction and relaxation mechanics of single myofibrils from left ventricular samples of one patient carrying the R403Q mutation to those from a healthy control heart. Tension generation and relaxation following sudden increase and decrease in [Ca2+] were much faster in the R403Q myofibrils with relaxation rates being the most affected parameters. The results show that the R403Q mutation leads to an apparent gain of protein function but a greater energetic cost of tension generation. Increased energy cost of tension generation may be central to the FHC disease process, help explain some unresolved clinical observations, and carry significant therapeutic implications.

(Received 28 April 2008; accepted after revision 14 June 2008; first published online 19 June 2008)
Corresponding author C. Poggesi: Dipartimento di Scienze Fisiologiche, Università di Firenze, Viale Morgagni 63, 50134 Firenze, Italia. Email: corrado.poggesi{at}unifi.it

This paper has online supplemental material.






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