The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy
Item Type: | Article |
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Title: | The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy |
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Creators Name: | Makarewich, C.A. and Munir, A.Z. and Schiattarella, G.G. and Bezprozvannaya, S. and Raguimova, O.N. and Cho, E.E. and Vidal, A.H. and Robia, S.L. and Bassel-Duby, R. and Olson, E.N. |
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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. |
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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 |
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Source: | eLife |
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ISSN: | 2050-084X |
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Publisher: | eLife Sciences Publications |
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Volume: | 7 |
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Page Range: | e38319 |
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Date: | 9 October 2018 |
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Official Publication: | https://doi.org/10.7554/eLife.38319 |
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PubMed: | View item in PubMed |
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