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

Catherine A. Makarewich, Amir Z. Munir, Gabriele G. Schiattarella, Svetlana Bezprozvannaya, Olga N. Raguimova, Ellen E. Cho, Alexander H. Vidal, Seth L. Robia, Rhonda S Bassel-Duby, Eric N Olson

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Calcium (Ca2+) dysregulation is a hallmark of heart failure and is characterized by impaired Ca2+ sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca2+-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 Ca2+ 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.

Original languageEnglish (US)
Article numbere38319
JournaleLife
Volume7
DOIs
StatePublished - Oct 9 2018

Keywords

  • SERCA
  • calcium
  • cardiac
  • cardiomyopathy
  • cell biology
  • contractility
  • heart failure
  • mouse

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy'. Together they form a unique fingerprint.

Cite this