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Do cardiac actin mutations lead to altered actomyosin interactions?

Marissa Dahari1,1, John F Dawson1,1

  • 1Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.

Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire
|July 22, 2015
PubMed

Insights

Mutations in the cardiac actin gene (ACTC) can cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). While some ACTC mutations alter actomyosin interactions, others do not appear to directly affect these core cardiac muscle functions.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Biophysics

Background:

  • Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are hypothesized to result from altered cardiac muscle contractility.
  • The cardiac actin gene (ACTC) is implicated in these conditions, but the precise molecular mechanisms remain under investigation.
  • Understanding how ACTC mutations affect the fundamental interaction between actin and myosin is crucial for elucidating disease pathogenesis.

Purpose of the Study:

  • To investigate the impact of eight cardiac actin (ACTC) mutations, found in HCM and DCM patients, on the actomyosin interaction.
  • To determine if specific ACTC mutations alter actin-activated myosin S1 ATPase rates, in vitro motility, and duty ratios.
  • To correlate observed molecular changes with potential mechanisms underlying HCM and DCM development.

Main Methods:

  • Biochemical assays measuring actin-activated myosin S1 ATPase rates for wild-type (WT) and mutant ACTC proteins.
  • In vitro motility assays were performed across varying ATP concentrations to assess kinetic parameters (KM, Vmax).
  • Calculation of the duty ratio, representing the proportion of time myosin spends attached to actin during the cross-bridge cycle, using a defined myosin step size.

Main Results:

  • The R312H ACTC mutation showed a decreased actin-activated myosin S1 ATPase rate compared to WT.
  • The E99K ACTC mutation exhibited a significantly higher ATPase rate and a doubled duty ratio compared to WT.
  • While E99K demonstrated altered kinetics (unchanged KM, decreased Vmax), other tested ACTC mutants did not show significant changes in basic actomyosin interactions.

Conclusions:

  • Mutations in the cardiac actin gene (ACTC) can lead to cardiomyopathies through diverse molecular mechanisms.
  • The E99K mutation's altered actomyosin kinetics, including increased ATP usage and tension, may contribute to HCM.
  • For several other ACTC mutants, disease development likely involves molecular mechanisms independent of direct alterations in the fundamental actin-myosin interaction.

Keywords:
actine cardiaqueactine-myosineactomyosincardiac actincardiomyopathie hypertrophiqueduty ratiofacteur de marchehypertrophic cardiomyopathymutations

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