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

• Published in: eLife Vol. 7
• Main Authors: Makarewich, Catherine A, Munir, Amir Z, Schiattarella, Gabriele G, Bezprozvannaya, Svetlana, Raguimova, Olga N, Cho, Ellen E, Vidal, Alexander H, Robia, Seth L, Bassel-Duby, Rhonda, Olson, Eric N
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 09.10.2018; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adenosine triphosphatase; Analysis; Animal experimentation; Animals; ATPases; Ca2+-transporting ATPase; calcium; Calcium (reticular); Calcium sequestration; Calcium-Binding Proteins - metabolism; cardiac; Cardiac function; Cardiomyopathy; Cardiomyopathy, Dilated - physiopathology; Cardiovascular disease; Cell Biology; Congestive cardiomyopathy; contractility; Dilated cardiomyopathy; Disease Models, Animal; Enzymes; Gene Knockout Techniques; Heart; Heart cells; Heart diseases; Heart failure; Heart Failure - prevention & control; Homeostasis; House mouse; Immunoglobulins; LIM Domain Proteins - deficiency; Medical research; Mice, Knockout; Muscle contraction; Muscle Proteins - deficiency; Myocardial Contraction - drug effects; Myocardial diseases; Peptides; Peptides - metabolism; Phospholamban; Prevention; Protein expression; Proteins; Sarcoplasmic reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA; United States > US; heart failure; mouse; calcium; cell biology; contractility; SERCA; cardiomyopathy; cardiac
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.38319

Calcium (Ca ) dysregulation is a hallmark of heart failure and is characterized by impaired Ca sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca -ATPase (SERCA). We recently discovered a micropeptide named DWORF ( arf pen eading rame) 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 Ca 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.