| First Author | Makarewich CA | Year | 2018 |
| Journal | Elife | Volume | 7 |
| PubMed ID | 30299255 | Mgi Jnum | J:274777 |
| Mgi Id | MGI:6304509 | Doi | 10.7554/eLife.38319 |
| Citation | Makarewich CA, et al. (2018) The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy. Elife 7:e38319 |
| abstractText | 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. |
