Prolonged Ca2+ and Force Transients in Myosin RLC Transgenic Mouse Fibers Expressing Malignant and Benign FHC Mutations

Ying Wang, Yuanyuan Xu, W. Glenn L. Kerrick, Yingcai Wang, Georgianna Guzman, Zoraida Diaz-Perez, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Clinical studies have revealed that mutations in the ventricular myosin regulatory light chain (RLC) lead to the development of familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular hypertrophy, myofibrillar disarray and sudden cardiac death. While mutations in other contractile proteins have been studied widely by others, there is no report elucidating the mechanism(s) associated with FHC-linked RLC mutations. In this study, we have assessed the functional consequences of two RLC mutations, R58Q and N47K, in transgenic mice. Clinical phenotypes associated with these mutations included inter-ventricular hypertrophy, abnormal ECG findings and the R58Q mutation caused multiple cases of premature sudden cardiac death. Simultaneous measurements of the ATPase and force in transgenic skinned papillary muscle fibers from mutated versus control mice showed an increase in the Ca2+ sensitivity of ATPase and steady-state force only in R58Q fibers. The calculated energy cost or rate of dissociation of force generating myosin cross-bridges (ATPase/force ratio) plotted as a function of activation state was the same in all groups of fibers. Both mutations caused prolonged [Ca2+] transients in electrically stimulated intact papillary muscles; however, the R58Q mutation also resulted in a significantly prolonged force transient. Our results suggest that the phenotypes of FHC observed in patients harboring these RLC mutations correlate with the extent of physiological changes monitored in transgenic fibers. Cardiac hypertrophy observed in patients is most likely caused by the activation of compensatory mechanisms ensuing from higher workloads due to incomplete relaxation as evidenced by prolonged [Ca2+] transients for both N47K and R58Q fibers. Furthermore, the poor prognosis of the R58Q patients may be associated with more severe diastolic dysfunction due to the slower off-rate of Ca2+ from troponin C leading to longer force and [Ca2+] transients and increased Ca2+ sensitivity of ATPase and force.

Original languageEnglish (US)
Pages (from-to)286-299
Number of pages14
JournalJournal of molecular biology
Volume361
Issue number2
DOIs
StatePublished - Aug 11 2006

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Keywords

  • ATPase/force
  • cardiac hypertrophy
  • intact papillary muscles
  • mutations, [Ca] and force transients
  • skinned fibers

ASJC Scopus subject areas

  • Virology

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