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The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy.

eLife (2018-10-10)
Catherine A Makarewich, Amir Z Munir, Gabriele G Schiattarella, Svetlana Bezprozvannaya, Olga N Raguimova, Ellen E Cho, Alexander H Vidal, Seth L Robia, Rhonda Bassel-Duby, Eric N Olson
RÉSUMÉ

Calcium (Ca2+) dysregulation is a hallmark of heart failure and is characterized by impaired Ca2+ sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca2+-ATPase (SERCA). We recently discovered a micropeptide named DWORF (DWarf Open Reading Frame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to genetic deletion of the muscle-specific LIM domain protein (MLP), we show that DWORF overexpression restores cardiac function and prevents the pathological remodeling and Ca2+ dysregulation classically exhibited by MLP knockout mice. Our results establish DWORF as a potent activator of SERCA within the heart and as an attractive candidate for a heart failure therapeutic.

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Sigma-Aldrich
3-Maleimidobenzoic acid N-hydroxysuccinimide ester, crystalline
Sigma-Aldrich
Anti-Calcium Channel Antibody, Voltage Gated α 1C, Chemicon®, from rabbit