Abstract

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During wound healing, myogenic satellite cells or myoblasts fuse within the damaged myotubes in the presence of serum. Before the fusion, myoblasts undergo a series of steps including multiplication to a greater number, shutting off the growth-promoting signals, expressing myogenic proteins, degrading myogenic inhibitors, and upregulating the expression of other muscle-specific proteins that are involved in the survival, migration, alignment, and fusion into myotubes. During differentiation of C2C12 myoblasts into multinucleated myotubes, the expression of eukaryotic initiation factor 2 (eIF2)-associated glycoprotein p67, increases and its level maximizes at the time of myoblasts fusion into myotubes. During this time of differentiation, p67 dissociates from eIF2 and associates with extracellular signal-regulated kinases 1 and 2 (ERK1/2). Dissociation from eIF2 leads to high levels of phosphorylation of smallest -subunit of eIF2 that suppresses the rates of global protein synthesis. Association of p67 with ERK1/2 kinases leads to the inhibition of activation and activity of the later kinases and subsequently this causes the shutting off the growth-promoting signal to myoblasts. P67 has intermolecular and intra-molecular proteolysis activity. This activity is not only involved in the degradation of certain cell cycle regulatory proteins, cyclins and Cdks both in myoblasts and in myotubes, it is also involved in the degradation of potent growth-promoting proteins like, myristoylated alanine-rich C kinase substrate (MARCKS) and focal adhesion kinase (FAK). By downregulating the expression and activity of the later proteins, p67 possibly enhances myoblasts’ actin cytoskeleton dynamics, migration, and alignment before fusion into myotubes. In contrast, p67 is also involved in the upregulated expression and activity of cPKC that has the ability to fuse myoblasts into myotubes in the presence of serum. In addition, increased expression of p67 during differentiation is involved in the upregulated expression and activity of p21-activating kinase 1 (Pak1), which is required for the motility and glucose homeostasis of skeletal muscles both in murine and human. Altogether, our findings suggest that p67 is involved in actin cytoskeleton dynamics, survival, migration, and alignment of myoblasts while fusing into multinucleated myotubes.

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