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

  1. Catherine A Makarewich
  2. Amir Z Munir
  3. Gabriele G Schiattarella
  4. Svetlana Bezprozvannaya
  5. Olga N Raguimova
  6. Ellen E Cho
  7. Alexander H Vidal
  8. Seth L Robia
  9. Rhonda Bassel-Duby
  10. Eric N Olson  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Loyola University Chicago, United States
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Cite this article as: eLife 2018;7:e38319 doi: 10.7554/eLife.38319

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.

Article and author information

Author details

  1. Catherine A Makarewich

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Amir Z Munir

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gabriele G Schiattarella

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Svetlana Bezprozvannaya

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Olga N Raguimova

    Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ellen E Cho

    Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alexander H Vidal

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Seth L Robia

    Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rhonda Bassel-Duby

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Eric N Olson

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Eric.Olson@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1151-8262

Funding

National Institutes of Health (R01 (HL-130253))

  • Rhonda Bassel-Duby
  • Eric N Olson

Welch Foundation (Research Grant)

  • Eric N Olson

Fondation Leducq (Research Grant)

  • Eric N Olson

National Institutes of Health (R01 (HD-087351))

  • Eric N Olson

National Institutes of Health (R01 (HL-092321))

  • Seth L Robia

National Institutes of Health (F32 (HL-129674))

  • Catherine A Makarewich

National Institutes of Health (K99 (HL-141630))

  • Catherine A Makarewich

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal work described in this manuscript has been approved and conducted under the oversight of the UT Southwestern Institutional Animal Care and Use Committee (IACUC). All of the animals were handled according to approved IACUC protocols (#2017-102269 and #2016-101833) of the UT Southwestern Medical Center.

Reviewing Editor

  1. Gordana Vunjak-Novakovic, Columbia University, United States

Publication history

  1. Received: May 12, 2018
  2. Accepted: September 26, 2018
  3. Accepted Manuscript published: October 9, 2018 (version 1)

Copyright

© 2018, Makarewich et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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