A micropeptide encoded by a putative long noncoding RNA regulates muscle performance

Douglas M. Anderson, Kelly M. Anderson, Chi Lun Chang, Catherine A. Makarewich, Benjamin R. Nelson, John R. McAnally, Prasad Kasaragod, John M. Shelton, Jen Liou, Rhonda Bassel-Duby, Eric N. Olson

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)595-606
Number of pages12
JournalCell
Volume160
Issue number4
DOIs
StatePublished - Feb 12 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Anderson, D. M., Anderson, K. M., Chang, C. L., Makarewich, C. A., Nelson, B. R., McAnally, J. R., Kasaragod, P., Shelton, J. M., Liou, J., Bassel-Duby, R., & Olson, E. N. (2015). A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell, 160(4), 595-606. https://doi.org/10.1016/j.cell.2015.01.009