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PMID: 25640239 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell ·Vol. 160 ·No. 4 ·2015-02-12 ·Pages 595-606

Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, Kasaragod P, Shelton JM, Liou J, Bassel-Duby R, Olson EN

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 Ca(2+) uptake into the sarcoplasmic reticulum (SR). MLN interacts directly with SERCA and impedes Ca(2+) 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 Ca(2+) 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.

MeSH Terms
Amino Acid Sequence Animals Base Sequence Calcium/metabolism Calcium-Binding Proteins/metabolism Humans Male Mice Models, Molecular Molecular Sequence Data Muscle Proteins/chemistry,genetics,metabolism Muscle, Skeletal/cytology,metabolism Myocardium/metabolism Protein Structure, Secondary Proteolipids/metabolism RNA, Long Noncoding/genetics,metabolism Sarcoplasmic Reticulum/metabolism Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism Sequence Alignment
Chemicals
Calcium-Binding Proteins Muscle Proteins Proteolipids RNA, Long Noncoding myoregulin, human myoregulin, mouse phospholamban sarcolipin Sarcoplasmic Reticulum Calcium-Transporting ATPases Calcium
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Anderson Douglas M
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Anderson Kelly M
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Chang Chi-Lun
Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Makarewich Catherine A
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Nelson Benjamin R
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
McAnally John R
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Kasaragod Prasad
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Shelton John M
Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Liou Jen
Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Bassel-Duby Rhonda
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Olson Eric N
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA. Electronic address: [email protected].
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2015.01.009
Email
[email protected]
Published
2015-02-12
Epub
2015-00-29
Pages
595-606
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4356254
Subset
IM
Grants
NHLBI NIH HHS · R01 HL077439 · United States
NIDDK NIH HHS · R01 DK099653 · United States
NIDDK NIH HHS · DK-099653 · United States
NHLBI NIH HHS · U01 HL100401 · United States
NHLBI NIH HHS · R01 HL053351 · United States
NHLBI NIH HHS · R01 HL111665 · United States
NHLBI NIH HHS · HL-077439 · United States
NHLBI NIH HHS · U01-HL-100401 · United States
NHLBI NIH HHS · HL-111665 · United States
NHLBI NIH HHS · HL-093039 · United States
NIAMS NIH HHS · 1F30AR067094-01 · United States
NIAMS NIH HHS · F30 AR067094 · United States
NHLBI NIH HHS · R01 HL093039 · United States
Corrections
CommentIn
PMID: 25863244
External Links
PubMed source DOI: 10.1016/j.cell.2015.01.009 PMC Full Text View journal details
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