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Abstract 571: MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy by Dysregulating Myosin: Implications for Therapy

Authors :
Christopher N Toepfer
Hiroko Wakimoto
Amanda C Garfinkel
Barbara McDonough
Dan Liao
Jianming Jiang
Angela Tai
Josh Gorham
Ida G Lund
Mingyue Lun
Thomas L Lynch
Sakthivel Sadayappan
Charles S Redwood
Hugh Watkins
Jonathan Seidman
Christine Seidman
Source :
Circulation Research. 123
Publication Year :
2018
Publisher :
Ovid Technologies (Wolters Kluwer Health), 2018.

Abstract

The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin binding protein-C; cMyBPC) or myosin missense mutations cause hyper-contractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches we explored how depletion of cMyBPC altered sarcomere function. We demonstrate that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM) normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation - enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across all phases of the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in DCM patients, while inhibiting myosin by MYK-461 should benefit the substantial proportion of HCM patients with MYBPC3 mutations.

Details

ISSN :
15244571 and 00097330
Volume :
123
Database :
OpenAIRE
Journal :
Circulation Research
Accession number :
edsair.doi...........3cf320840e83064d69f587f822fdcdff