Abstract 335: Regulation of Muscle Contractility by a Family of SERCA-Inhibitory Micropeptides

Abstract

Functional micropeptides can be concealed within RNA transcripts that have been putatively annotated as non-coding. We recently discovered a muscle-specific micropeptide, named myoregulin (MLN), that inhibits the activity of SERCA, the membrane pump that controls muscle relaxation by regulating Ca2+ uptake into the sarcoplasmic reticulum (SR). Genetic deletion of MLN in mice enhances Ca2+ handling in skeletal muscle and improves exercise performance. MLN shares structural and functional similarity with phospholamban (PLN) and sarcolipin (SLN), two well-studied micropeptides that regulate cardiac contractility and disease. Here we identify an additional member of this micropeptide family, named endoregulin (ELN), that specifically overlaps with the expression of SERCA3, the dominant Ca2+ ATPase in endothelial cells that controls the contractility of vascular and visceral smooth muscles. ELN encodes a single transmembrane alpha helix that localizes to the endoplasmic reticulum (ER), where it forms a stable complex with SERCA3. In cell based assays, ELN inhibits SERCA-dependent Ca2+ uptake into the ER and controls ER calcium levels. Due to the essential role of SERCA3 in regulating vascular smooth muscle contractility, ELN represents a potential regulator of vascular tone and novel therapeutic target for the treatment of cardiovascular disease.