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Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin

Christopher N Toepfer1,2,3, Hiroko Wakimoto4,5, Amanda C Garfinkel4

  • 1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. christopher_toepfer@hms.harvard.edu cseidman@genetics.med.harvard.edu.

Science Translational Medicine
|January 25, 2019
PubMed

Insights

Loss of cardiac myosin-binding protein C (cMyBPC) increases heart muscle contractility. Inhibiting myosin function or ATPase activity may treat hypertrophic cardiomyopathy (HCM) caused by MYBPC3 mutations.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Genetic Heart Disease

Background:

  • Truncating mutations in MYBPC3 and myosin missense mutations are linked to hypertrophic cardiomyopathy (HCM).
  • The precise mechanisms driving hypercontractility and impaired relaxation in HCM due to these mutations remain unclear.
  • Cardiac myosin-binding protein C (cMyBPC) plays a crucial role in sarcomere function, but its precise contribution to HCM pathophysiology is not fully elucidated.

Purpose of the Study:

  • To investigate how the depletion of cMyBPC affects sarcomere function and myosin dynamics.
  • To explore the relationship between cMyBPC levels, myosin contractility, and relaxation in the context of HCM.
  • To evaluate potential therapeutic strategies targeting myosin function for HCM treatment.

Main Methods:

  • Genetic manipulation to deplete cMyBPC in cardiomyocytes.
  • Biochemical assays to assess myosin function and contractility.
  • Utilized a specific myosin missense variant (F764L) associated with dilated cardiomyopathy (DCM).
  • Employed MYK-461, a pharmacologic inhibitor of myosin ATPase, in cellular and animal models.

Main Results:

  • Stepwise reduction of cMyBPC led to increased myosin contractility.
  • Attenuating myosin function with the F764L variant normalized hypercontractility caused by cMyBPC depletion.
  • cMyBPC depletion altered myosin's dynamic conformations, favoring ATP hydrolysis and reducing energy-conserving states.
  • MYK-461 treatment rescued relaxation deficits and normalized contractility in cardiomyocytes with MYBPC3 mutations.

Conclusions:

  • cMyBPC exhibits dosage-dependent effects on myosin function throughout the cardiac cycle.
  • These findings elucidate the pathophysiological mechanisms by which MYBPC3 truncations contribute to HCM.
  • Therapeutic strategies aimed at modulating myosin activity, such as using MYK-461, show promise for treating HCM associated with MYBPC3 mutations.

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