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The myosin-activated thin filament regulatory state, M⁻-open: a link to hypertrophic cardiomyopathy (HCM)

Sherwin S Lehrer1, Michael A Geeves

  • 1, 4416 Great Meadow Rd, Dedham, MA, USA, Sherwin.lehrer@gmail.com.

Journal of Muscle Research and Cell Motility
|April 18, 2014
PubMed

Insights

Mutations in sarcomeric thin filament proteins causing hypertrophic (HCM) and restrictive cardiomyopathies may be linked to the open state in muscle regulation theory. This open state explains increased Ca(2+) sensitivity and basal activity seen in HCM.

Area of Science:

  • Muscle physiology
  • Cardiovascular research
  • Molecular biology

Background:

  • Hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathies are linked to mutations in sarcomeric thin filament proteins.
  • The three-state muscle regulation theory describes muscle activation states.

Purpose of the Study:

  • To propose a link between cardiomyopathies and the open state of the three-state muscle regulation theory.
  • To explain HCM characteristics using a myosin-induced open state model.

Main Methods:

  • Review of existing literature on sarcomeric protein mutations and muscle regulation.
  • Modeling based on the three-state theory of muscle regulation.

Main Results:

  • HCM-associated mutations exhibit increased Ca(2+) sensitivity, basal activity, and decreased cooperativity.
  • A myosin-induced open state (M (-) ) contributes to elevated basal activity and competes with Ca(2+)-activated pathways.
  • Mutations weakening troponin I-tropomyosin-actin binding can alter the closed/blocked equilibrium, producing HCM characteristics.
  • In the M (-) state, Ca(2+) influences troponin C's N-terminal equilibrium without affecting activity.

Conclusions:

  • The myosin-induced open state provides a unifying explanation for HCM and restrictive cardiomyopathies.
  • Understanding these molecular mechanisms can inform therapeutic strategies for cardiomyopathies.

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