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

Authors

  • C.A. Makarewich
  • A.Z. Munir
  • G.G. Schiattarella
  • S. Bezprozvannaya
  • O.N. Raguimova
  • E.E. Cho
  • A.H. Vidal
  • S.L. Robia
  • R. Bassel-Duby
  • E.N. Olson

Journal

  • eLife

Citation

  • eLife 7: e38319

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.


DOI

doi:10.7554/eLife.38319