Membrane-bound delta-like 1 homolog (Dlk1) promotes while soluble Dlk1 inhibits myogenesis in C2C12 cells

• Soluble DLK1 inhibits myogenic cell differentiation.
• Membrane-bound DLK1 promotes hypertrophic muscle development.
• Genes affecting myogenesis are differently regulated by DLK1 isoforms.
• Regulation of DLK1 expression and cleavage is critical for muscle development.
• Abnormal muscle development in mouse UPD12 could be explained by our study.

Delta-like 1 homolog (Dlk1) is important in myogenesis. However, the roles of different Dlk1 isoforms have not been investigated. In C2C12 cell lines producing different Dlk1 isoforms, membrane-bound Dlk1 promoted the hypertrophic phenotype and a higher fusion rate, whereas soluble Dlk1 inhibited myotube formation. Inversed expression patterns of genes related to myogenic differentiation further support these phenotypic changes. In addition, temporal expression and balance between the Dlk1 isoforms have a regulatory role in myogenesis in vivo. Collectively, Dlk1 isoforms have distinctive effects on myogenesis, and its regulation during myogenesis is critical for normal muscle development.