A micropeptide encoded by a putative long noncoding RNA regulates muscle performance
Open accessAbstract
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.
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Many regions previously annotated as non-coding actually produce functional micropeptides involved in cellular regulation.
“Recent studies have shown that many regions previously annotated as non-coding actually produce functional micropeptides involved in cellular regulation [102].”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [102]
The Introduction reports that genome-wide studies suggest hundreds of functional micropeptides may be encoded in annotated non-coding RNAs, and describes this paper’s verified example, myoregulin. The Discussion cautions that only a few such micropeptides have been functionally verified in vivo. Thus the source supports the phenomenon and its regulatory role, but not the claim that many regions have been shown to produce functional micropeptides. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome transcripts originally classified as putative lncRNAs encode hidden micropeptides that critically regulate muscle performance and intracellular signaling in murine models.
“For instance, recent discoveries in murine models reveal that some transcripts originally classified as putative lncRNAs encode hidden micropeptides that critically regulate muscle performance and intracellular signaling [196].”
From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [196]
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- Authors
- 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.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Olson, Eric N.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 4
- Pages
- 595-606
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4356254
- OpenAlex
- W2085220756
- Cited by
- 1,216
- References
- 57
- Citations by year
- 2026: 61 · 2025: 101 · 2024: 90 · 2023: 104 · 2022: 119 · 2021: 128 · 2020: 149 · 2019: 116 · 2018: 118 · 2017: 103 · 2016: 73 · 2015: 53
- FWCI
- 50.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u01hl100401-07)
- National Heart, Lung, and Blood Institute (R01HL111665, R01HL077439, HL- 111665, U01-HL-100401, R01HL053351, R01HL093039, HL077439, HL093039)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK099653, R01DK099653)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (F30AR067094)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- micropeptides, long non-coding RNA, SERCA, calcium handling, sarcoplasmic reticulum, skeletal muscle, exercise performance, phospholamban, sarcolipin, muscle relaxation, gene deletion
- MeSH terms
- Phospholamban, Amino Acid Sequence, Animals, Base Sequence, Calcium, Calcium-Binding Proteins, Humans, Male, Models, Molecular, Molecular Sequence Data, Muscle Proteins, Myocardium, Proteolipids, Sarcoplasmic Reticulum, Sequence Alignment, Protein Structure, Secondary, Muscle, Skeletal, Mice, Sarcoplasmic Reticulum Calcium-Transporting ATPases, RNA, Long Noncoding
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