Alternative titles; symbols
HGNC Approved Gene Symbol: MRLN
Cytogenetic location: 10q21.2 Genomic coordinates (GRCh38): 10:59,736,692-59,753,455 (from NCBI)
Muscle stimulation causes release of Ca(2+) from sarcoplasmic reticulum (SR) stores, resulting in actomyosin cross-bridging within the sarcomere to generate contractile force. Reuptake of Ca(2+) into SR by the Ca(2+) ATPase SERCA (see ATP2A1, 108730) is necessary for muscle relaxation and restoration of SR Ca(2+) stores. MRLN is a short peptide that functions as an inhibitor of SERCA in skeletal muscle (summary by Anderson et al., 2015).
While analyzing skeletal muscle-specific long intergenic noncoding RNAs (LINCs), Anderson et al. (2015) identified a 427-nucleotide LINC with the potential to encode myoregulin (MLN), a conserved 46-amino acid peptide. MLN was predicted to form a type II single-pass transmembrane protein with 19 N-terminal amino acids exposed to the cytosol and 3 C-terminal residues in the lumen. MLN showed strong structural resemblance to phospholamban (PLN; 172405) and sarcolipin (SLN; 602203). Northern blot analysis of 15 mouse tissues detected Mln expression in skeletal muscle only. In situ hybridization of mouse embryos detected Mln expression in the myotomal compartment of somites. During fetal and adult stages, Mln was robustly expressed in all skeletal muscles, but not in cardiac or smooth muscles. Mln was also detected in mouse C2C12 myoblasts and myotubes, but not in mouse 10T1/2 fibroblasts. Electroporation of mice with fluorescence-tagged mouse Mln detected localization of Mln to the SR in an alternating pattern with the myosin A band, and overlapping with Serca1. In vitro transcription and translation resulted in expression of a peptide with an apparent molecular mass of approximately 5 kD. Database analysis revealed orthologs of MLN in vertebrates and invertebrates.
By modeling possible interactions of mouse Mln with Serca1, Anderson et al. (2015) found that Mln bound a groove in Serca1 in a manner identical to the interactions of Pln or Sln with Serca1. Coimmunoprecipitation analysis confirmed that epitope-tagged Mln formed a stable complex with Serca1 and with 2 isoforms of Serca2 (ATP2A2; 108740). Coexpression of Mln with Serca1 reduced the rate of Ca(2+) reuptake in HEK293 cells compared with cells expressing Serca1 alone. Overexpression of Mln in C2C12 myoblasts significantly decreased peak Ca(2+) release from SR. Reporter gene assays, EMSA, and ChIP analysis revealed functional MYOD1 (159970)- and MEF2A (600660)-binding sites in the Mln 5-prime flanking region, suggesting that these transcription factors regulate Mln expression.
Anderson et al. (2015) determined that the MRLN gene contains 3 exons and spans 16.5 kb.
Anderson et al. (2015) reported that both the human and mouse MRLN genes map to chromosome 10.
Hartz (2015) mapped the MRLN gene to chromosome 10q21.2 based on an alignment of the MRLN sequence (GenBank BG210823) with the genomic sequence (GRCh38).
Anderson et al. (2015) obtained Mln -/- mice in the expected mendelian ratio. Mln -/- mice showed no obvious morphologic differences in body or muscle weights compared with wildtype. Histologic analysis revealed no obvious difference in fiber type identity or myofiber size between Mln -/- and wildtype mice; however, when forced to run a treadmill, Mln -/- mice ran 55% further than wildtype before exhaustion. Primary hindlimb muscle myoblasts of Mln -/- mice showed significantly elevated SR Ca(2+) compared with wildtype.
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. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160: 595-606, 2015. [PubMed: 25640239] [Full Text: https://doi.org/10.1016/j.cell.2015.01.009]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/26/2015.