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

Abstract

Summary Functional micropeptides can be concealed within RNAs that appear to be non-coding. We discovered a conserved micropeptide, that we named myoregulin (MLN), encoded by a skeletal muscle-specific RNA annotated as a putative long non-coding 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 non-coding.

Hidden Peptides Encoded by Putative Noncoding RNAs

“…The myoregulin (MLN) transcript was originally identified as a skeletal muscle-specific lncRNA conserved among vertebrates (LINC00948 in human and 2310015B20Rik in mouse), but it possesses a conserved ORF for a 46-amino acid peptide (Anderson et al, 2015). The translation of MLN RNA was confirmed by both in vitro translation and in vivo FLAG-tag knock-in assays.…”

“…3D). Mice deficient in MLN manifest enhanced Ca 2+ handling and skeletal muscle performance (Anderson et al, 2015).…”

“…Although lncRNAs do not harbor apparent open reading frames (ORFs) for proteins of >100 amino acids, recent studies have identified a subset of lncRNAs that actually encode polypeptides of <100 amino acids (Fig. 1A) (Anderson et al, 2015;Kondo et al, 2010;Matsumoto et al, 2017;Nelson et al, 2016;Pauli et al, 2014).…”

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

“…Myoregulin is a recently identified skeletal muscle-specific micropeptide sharing structural similarities with sarcolipin and phospholamban. Myoregulin interacts with SERCA1 and by so doing decreases the pump's activity [12]. Its deletion in mice enhances Ca 2+ handling and improves exercise performance, suggesting that myoregulin plays an important physiological role in regulating skeletal muscle Ca 2+ homeostasis.…”

“…The calculated frequency of RYR1 mutations is approximately 1:3000 making it one of the most commonly mutated genes associated with neuromuscular disorders [38][39][40]. A number of reviews concerning the frequency, disease associations and functional impact of RYR1 mutations have been published in recent years and the reader is referred to these for a more in depth description (for example see [12][13][14][15][16][17][18][19][20][21][22][23][24][41][42][43][44][45]). The disease phenotype resulting from RYR1 mutations largely depends on their location within the RYR1 coding sequence and whether the mutations are dominant or recessive.…”