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

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Item Type:Article
Title:The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy
Creators Name:Makarewich, C.A., Munir, A.Z., Schiattarella, G.G., Bezprozvannaya, S., Raguimova, O.N., Cho, E.E., Vidal, A.H., Robia, S.L., Bassel-Duby, R. and Olson, E.N.
Abstract:Calcium (Ca(2+)) dysregulation is a hallmark of heart failure and is characterized by impaired Ca(2+) sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca(2+)-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 Ca(2+) 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.
Keywords:Animal Disease Models, Calcium-Binding Proteins, Dilated Cardiomyopathy, Gene Knockout Techniques, Heart Failure, LIM Domain Proteins, Knockout Mice, Muscle Proteins, Myocardial Contraction, Peptides, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Animals, Mice
Source:eLife
ISSN:2050-084X
Publisher:eLife Sciences Publications
Volume:7
Page Range:e38319
Date:9 October 2018
Official Publication:https://doi.org/10.7554/eLife.38319
PubMed:View item in PubMed

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