Myomixer, a micropeptide, controls formation of skeletal muscle.
Recently the fusogenic micropeptide called myomixer was found to control the formation of mammalian skeletal muscles.
Researchers at the UTSW Medical Center in Dallas, Texas, used a genome-wide CRISPR genetic loss-of-function screen to identify genes required for myoblast fusion and myogenesis. The researchers identified the new regulator of myogenesis using 130,209 single-guide RNAs (sgRNA) in C2C12 myoblasts of a mouse muscle cell line.
First, the scientists reported that the gene Gm7325 is required for myoblast fusion. This gene is expressed in embryonic stem (ES) cells and germ cells. However, its function was not known until now.
Secondly, using the CRISPR screen, the scientists discovered an 84-amino acid muscle-specific peptide, named “myomixer.”
This peptide was previously predicted from an RNAseq intron as an uncharacterized precursor. Because of its expression coinciding with myoblast differentiation and its essential role in the fusion of skeletal muscle as well as for the formation of skeletal muscle during embryogenesis the scientists named it “myomixer.” In addition, the researchers reported that myomixer is localized in the plasma membrane. Myomixer promotes myoblast fusion and associates with myomaker, a fusogenic membrane protein.
According to Millay et al. (2016), Myomaker is the only identified muscle-specific protein required for myoblast fusion. CRISPR/Cas9 mutagenesis screening was used for structure-function analysis to understand the fusion process of skeletal muscle cells.
Amino acid sequence of myomixer as determined by Bi et al. (2017).
>NP_001302423.1 uncharacterized LOC101929726 precursor [Homo sapiens]
MPTPLLPLLLRLLLSCLLLPAARLARQYLLPLLRRLARRLGSQDMREALLGCLLFILSQRHSPDAGEASR
VDRLERRERLGPQK
>NP_001170939.1 uncharacterized LOC101929726 homolog isoform 1 [Mus musculus]
MPVPLLPMVLRSLLSRLLLPVARLARQHLLPLLRRLARRLSSQDMREALLSCLLFVLSQQQPPDSGEASR VDHSQRKERLGPQK
Alignment using BioEdit:
Skeletal muscle is the largest tissue in humans. Skeletal muscle accounts for approximately close to 40 % or more of human body mass.
Myogenesis refers to the formation of muscular tissue, usually during embryonic development. In general muscle fibers form from the fusion of myoblasts to form multi-nucleated fibers.
Muscle fibers are called myotubes. The formation of skeletal muscle occurs through fusion of embryotic muscle cells (myoblasts) forming multinucleated muscle fibers (myofibers). Skeletal muscles are made up of strings or bundles of muscle fibers. These are large cells which are approximately 50 μm in diameter and up to several centimeters long. These skeletal muscle bundles are formed by fusion of many individual muscle cells during development.
The fusion of myoblasts needs cell recognition, migration, adhesion, signaling, and the joining of different muscle cells. Extracellular calcium and changes in cell membrane topography and cytoskeletal organization are required for myoblast fusion. Several cell-surface and intracellular proteins are now known to mediate myoblast fusion. Also, myoblast fusion appears to be also regulated by activation of specific cell-signaling pathways. The activation of these pathways is essential for the fusion process and cytoskeletal rearrangement.
Formation of skeletal muscle begins with speciation of muscle cells induced by the myogenic transcription factors Pax7 and MyoD, followed by the expression of a large number of genes that establish muscle structure and function.
The Pax7 gene is a transcription factor and a member of the paired box (PAX) family. This gene family typically contain a paired box domain, and octapeptide, and a paired-type homeodomain. PAX family genes play critical roles during fetal development as well as in cancer growth.
The MyoD protein has a major role in regulating muscle cell differentiation. The expression of MyoD is necessary for the expression of muscle-related genes. MYOD1 encodes a nuclear protein belonging to the helix-loop-helix family of transcription factors. MYOD1 regulates muscle cell differentiation by inducing cell cycle arrest. It is also involved in muscle regeneration, and it activates its own transcription.
The fusion of mononucleated myoblasts, embryonic muscle cells containing one nucleus, forms multinucleated myofibers or fused muscle cells containing multiple nuclei.
When muscle cells are injured, healthy human muscle cells respond by activating pro-genitor cells, or muscle stem cells that can only develop into muscle fiber cells, present within adult muscles that now fuse to generate new myofibers or bundled muscle cells. However, components and the molecular basis of fusion of muscle cells are not yet fully defined or understood.
Reference
PENGPENG BI, ANDRES RAMIREZ-MARTINEZ, HUI LI, JESSICA CANNAVINO, JOHN R. MCANALLY, JOHN M. SHELTON, EFRAIN SÁNCHEZ-ORTIZ, RHONDA BASSEL-DUBY, ERIC N. OLSON; Control of muscle formation by the fusogenic micropeptide myomixer. Science 2017, 323-327. DOI: 10.1126/science.aam9361.
Millay DP, Gamage DG, Quinn ME, et al. Structure–function analysis of myomaker domains required for myoblast fusion. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(8):2116-2121. doi:10.1073/pnas.1600101113.}
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