Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice

Katarzyna Kazmierczak, Priya Muthu, Wenrui Huang, Michelle Jones, Yingcai Wang, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

FHC (familial hypertrophic cardiomyopathy) is a heritable form of cardiac hypertrophy caused by mutations in genes encoding sarcomeric proteins. The present study focuses on the A13T mutation in the human ventricular myosin RLC (regulatory light chain) that is associated with a rare FHC variant defined by mid-ventricular obstruction and septal hypertrophy.We generated heart-specific Tg (transgenic) mice with ∼10%of human A13T-RLC mutant replacing the endogenous mouse cardiac RLC. Histopathological examinations of longitudinal heart sections from Tg-A13T mice showed enlarged interventricular septa and profound fibrotic lesions compared with Tg-WT (wildtype), expressing the human ventricular RLC, or non-Tg mice. Functional studies revealed an abnormal A13T mutation-induced increase in isometric force production, no change in the force - pCa relationship and a decreased V max of the acto-myosin ATPase. In addition, a fluorescence-based assay showed a 3-fold lower binding affinity of the recombinant A13T mutant for the RLC-depleted porcine myosin compared with WT-RLC. These results suggest that the A13T mutation triggers a hypertrophic response through changes in cardiac sarcomere organization and myosin cross-bridge function leading to abnormal remodelling of the heart. The significant functional changes observed, despite a low level of A13T mutant incorporation into myofilaments, suggest a 'poison-peptide' mechanism of disease.

Original languageEnglish (US)
Pages (from-to)95-103
Number of pages9
JournalBiochemical Journal
Volume442
Issue number1
DOIs
StatePublished - Feb 15 2012

Keywords

  • A13T mutation
  • ATPase activity
  • Familial hypertrophic cardiomyopathy (FHC)
  • Fibrosis
  • Muscle fibre force
  • Myosin regulatory light chain (myosin RLC)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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