The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy
- University of Texas Southwestern Medical Center, United States
- Loyola University Chicago, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
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.
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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The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy
eLife 7:e38319.
https://doi.org/10.7554/eLife.38319
