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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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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
Summary
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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