Abstract
Fusion of myoblasts into multinucleated myofibers is crucial for skeletal muscle development and regeneration. However, the mechanisms controlling this process remain to be determined. Here we identified the involvement of a new extracellular matrix protein in myoblast fusion. Collagen XXV is a transmembrane-type collagen highly transcribed during early myogenesis when primary myofibers form. Limb muscles of E12.5 and E14.5 Col25a1−/− embryos show a clear defect in the formation of multinucleated myofibers. In cell culture, the cleaved soluble extracellular domain of the collagen XXV is sufficient to promote the formation of highly multinucleated myofibers. Col25a1 is transiently expressed during myogenic differentiation and Col25a1 transcripts are down-regulated in multinucleated myofibers by a muscle-specific microRNA, miR-499. Altogether, these findings indicate that collagen XXV is required in vivo and in vitro for the fusion of myoblasts into myofibers and give further evidence that microRNAs participate to the regulation of this process.
Highlights
Fusion of myoblasts into multinucleated myofibers is crucial for skeletal muscle development and regeneration
Analysis of forelimbs from E12.5 WT and Col25a1−/− embryos strongly suggests that collagen XXV is required for the formation of multinucleated myofibers during primary myogenesis (Fig. 1E)
This suggests that collagen XXV expression is important for myoblasts to properly fuse, we did detect multinucleated myofibers at later embryonic stages
Summary
Fusion of myoblasts into multinucleated myofibers is crucial for skeletal muscle development and regeneration. Skeletal muscle formation can be divided into several sequential events, as migration of muscle precursor cells (mpc), proliferation of myoblasts, cell cycle arrest, myoblast differentiation and fusion These different steps are characterized by the expression of muscle specific transcription factors, the muscle regulatory factors (MRFs), Myf[5], MyoD, myogenin and MRF4. Type XXV collagen is highly expressed in developing limb skeletal muscles and in differentiating C2C12 myotubes, suggesting a role in the myogenic differentiation[7]. This collagen belongs to the MACIT (membrane-associated collagens with interrupted triple helices) subset of the collagen superfamily, together with type XIII, XVII and XXIII collagens[8]. Col25a1 transcripts were detected in differentiating limb myofibers from early E11.5, long before muscle innervation, suggesting that this collagen could be involved in early myogenesis steps
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