A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance

Highlights

• Myoregulin is a micropeptide encoded by an annotated long noncoding RNA

• Myoregulin is a transmembrane alpha helix expressed only in skeletal muscle

• Myoregulin regulates Ca²⁺ handling by inhibiting the pump activity of SERCA

• Myoregulin KO mice show improved exercise performance and Ca²⁺ handling in muscle

Summary

Functional micropeptides can be concealed within RNAs that appear to be noncoding. We discovered a conserved micropeptide, which we named myoregulin (MLN), encoded by a skeletal muscle-specific RNA annotated as a putative long noncoding RNA. MLN shares structural and functional similarity with phospholamban (PLN) and sarcolipin (SLN), which inhibit SERCA, the membrane pump that controls muscle relaxation by regulating Ca²⁺ uptake into the sarcoplasmic reticulum (SR). MLN interacts directly with SERCA and impedes Ca²⁺ uptake into the SR. In contrast to PLN and SLN, which are expressed in cardiac and slow skeletal muscle in mice, MLN is robustly expressed in all skeletal muscle. Genetic deletion of MLN in mice enhances Ca²⁺ handling in skeletal muscle and improves exercise performance. These findings identify MLN as an important regulator of skeletal muscle physiology and highlight the possibility that additional micropeptides are encoded in the many RNAs currently annotated as noncoding.