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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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