Deciphering the role of a novel micropeptide in cardiac function and dysfunction

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 DESCRIPTION (provided by applicant): Ca2+ controls cardiac function by acting as the primary regulator of the sarcomeric contractile machinery and as a second messenger in the signal transduction pathways that control cardiac growth, metabolism and pathological remodeling. Ca2+ handling in striated muscle is tightly regulated by Ca2+ pumps in the sarcoplasmic reticulum (SR) and plasma membranes that maintain intracellular Ca2+ levels ~10,000-fold lower than extracellular and SR concentrations. Ca2+ release from the SR membrane transiently increases Ca2+ levels in the cytosol, triggering actomyosin cross-bridge formation within the sarcomere to generate contractile force. Reuptake of Ca2+ into the SR by sarcoplasmic reticulum Ca2+-ATPase (SERCA) is necessary for muscle relaxation and restores SR Ca2+ levels for subsequent contraction-relaxation cycles. SERCA thus serves as a central regulator of cardiac function, as well as the pathogenic signaling cascades that drive heart disease. The activity of SERCA in the heart is modulated by phospholamban (PLN), a tiny peptide that interacts with SERCA in the SR membrane and diminishes Ca2+ pump activity. Recently, we discovered that a cardiac- specific RNA annotated as a long noncoding RNA actually encodes a previously unrecognized micropeptide, which we named DWORF (Dwarf Open Reading Frame). DWORF is localized to the SR of cardiomyocytes and interacts with SERCA. DWORF is among the most dramatically down-regulated proteins in failing hearts, pointing to its potential involvement in the response of the heart to stress and contractile dysfunction. The overall goals of this project are to define the functions of DWORF and to decipher the mechanisms that govern its expression in normal and diseased hearts. Manipulation of the activity of this novel micropeptide represents a potential strategy to enhance cardiac contractility in the setting of heart disease. The discovery of DWORF also provides a new inroad into our understanding of the signaling mechanisms involved in the control of cardiac function and suggests a previously unrecognized role for micropeptides in the control of cardiac physiology and pathology.