@article{5179136d071448d598a0e938a37f41ff,
title = "The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy",
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.",
author = "Makarewich, {Catherine A.} and Munir, {Amir Z.} and Schiattarella, {Gabriele G.} and Svetlana Bezprozvannaya and Raguimova, {Olga N.} and Cho, {Ellen E.} and Vidal, {Alexander H.} and Robia, {Seth L.} and Bassel-Duby, {Rhonda S} and Olson, {Eric N}",
note = "Funding Information: We thank E Kranias (University of Cincinnati College of Medicine) for generously providing the phos-pholamban transgenic mice. We thank J Cabrera for graphics, W Tan for echocardiography, the Molecular Pathology Core under the direction of J Richardson at the University of Texas Southwestern Medical Center for help with histology, and the Electron Microscopy Core at the University of Texas Southwestern Medical Center under the direction of K Luby-Phelps for help with EM sample processing. This work was supported by grants from the NIH (HL-130253, HD-087351, HL-138426, HL-092321 and AR-067294), Fondation Leducq Networks of Excellence, and the Robert A Welch Foundation (grant 1–0025 to ENO). CAM was supported by a National Heart, Lung, and Blood Institute, NIH Ruth L Kirschstein National Research Service Award (NRSA) (F32HL129674) and a National Heart, Lung, and Blood Institute, NIH Pathway to Independence Award (K99HL141630). GGS was supported by an American Heart Association and the Theodore and Beulah Beasley Foundation grant (18POST34060230). Funding sources were not involved in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: We thank E Kranias (University of Cincinnati College of Medicine) for generously providing the phos-pholamban transgenic mice. We thank J Cabrera for graphics, W Tan for echocardiography, the Molecular Pathology Core under the direction of J Richardson at the University of Texas Southwestern Medical Center for help with histology, and the Electron Microscopy Core at the University of Texas Southwestern Medical Center under the direction of K Luby-Phelps for help with EM sample processing. This work was supported by grants from the NIH (HL-130253, HD-087351, HL-138426, HL-092321 and AR-067294), Fondation Leducq Networks of Excellence, and the Robert A Welch Foundation (grant 1?0025 to ENO). CAM was supported by a National Heart, Lung, and Blood Insti-tute, NIH Ruth L Kirschstein National Research Service Award (NRSA) (F32HL129674) and a National Heart, Lung, and Blood Institute, NIH Pathway to Independence Award (K99HL141630). GGS was supported by an American Heart Association and the Theodore and Beulah Beasley Foundation grant (18POST34060230). Funding sources were not involved in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Makarewich et al.",
year = "2018",
doi = "10.7554/ELIFE.38319",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}