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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.<\/jats:p>","DOI":"10.7554\/elife.38319","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T20:00:18Z","timestamp":1539028818000},"source":"Crossref","is-referenced-by-count":135,"title":["The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6907-4401","authenticated-orcid":true,"given":"Catherine A","family":"Makarewich","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir Z","family":"Munir","sequence":"additional","affiliation":[{"name":"Department of 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States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen E","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander H","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth L","family":"Robia","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda","family":"Bassel-Duby","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Hamon Center for Regenerative Science and 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