The R403Q mutation in beta-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 [Ca(2+)] 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.

The familial hypertrophic cardiomyopathy-associated myosin mutation R403Q accelerates tension generation and relaxation of human cardiac myofibrils / Belus, ALEXANDRA ANNA SOPHIE; Piroddi, Nicoletta; Scellini, Beatrice; Tesi, Chiara; D'Amati, G.; Girolami, F.; Yacoub, Magdi; Cecchi, Franco; Olivotto, I.; Poggesi, Corrado. - In: THE JOURNAL OF PHYSIOLOGY. - ISSN 0022-3751. - STAMPA. - 586:(2008), pp. 3639-3644. [10.1113/jphysiol.2008.155952]

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

BELUS, ALEXANDRA ANNA SOPHIE;PIRODDI, NICOLETTA;SCELLINI, BEATRICE;TESI, CHIARA;YACOUB, MAGDI;CECCHI, FRANCO;OLIVOTTO, IACOPO;POGGESI, CORRADO
2008

Abstract

The R403Q mutation in beta-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 [Ca(2+)] 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.
2008
586
3639
3644
Belus, ALEXANDRA ANNA SOPHIE; Piroddi, Nicoletta; Scellini, Beatrice; Tesi, Chiara; D'Amati, G.; Girolami, F.; Yacoub, Magdi; Cecchi, Franco; Olivotto...espandi
File in questo prodotto:
File Dimensione Formato  
Belus2008JPhys.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 240.78 kB
Formato Adobe PDF
240.78 kB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/328149
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 91
  • ???jsp.display-item.citation.isi??? 85
social impact