Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and -15 facilitates myoblast fusion

Skeletal muscle development and regeneration requires the fusion of myoblasts into multinucleated myotubes. Because the enzymatic proteolysis of a hyaluronan and versican-rich matrix by ADAMTS versicanases is required for developmental morphogenesis, we hypothesized that the clearance of versican may facilitate the fusion of myoblasts during myogenesis. Here, we used transgenic mice and an in vitro model of myoblast fusion, C2C12 cells, to determine a potential role for ADAMTS versicanases. Versican processing was observed during in vivo myogenesis at the time when myoblasts were fusing to form multinucleated myotubes. Relevant ADAMTS genes, chief among them Adamts5 and Adamts15, were expressed both in developing embryonic muscle and differentiating C2C12 cells. Reducing the levels of Adamts5 mRNA in vitro impaired myoblast fusion, which could be rescued with catalytically active but not the inactive forms of ADAMTS5 or ADAMTS15. The addition of inactive ADAMTS5, ADAMTS15, or full-length V1 versican effectively impaired myoblast fusion. Finally, the expansion of a hyaluronan and versican-rich matrix was observed upon reducing the levels of Adamts5 mRNA in myoblasts. These data indicate that these ADAMTS proteinases contribute to the formation of multinucleated myotubes such as is necessary for both skeletal muscle development and during regeneration, by remodeling a versican-rich pericellular matrix of myoblasts. Our study identifies a possible pathway to target for the improvement of myogenesis in a plethora of diseases including cancer cachexia, sarcopenia, and muscular dystrophy.

The ADAMTS hyalectanase family: biological insights from diverse species

The a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs (ADAMTS) family of metzincins are complex secreted proteins that have diverse functions during development. The hyalectanases (ADAMTS1, 4, 5, 8, 9, 15 and 20) are a subset of this family that have enzymatic activity against hyalectan proteoglycans, the processing of which has important implications during development. This review explores the evolution, expression and developmental functions of the ADAMTS family, focusing on the ADAMTS hyalectanases and their substrates in diverse species. This review gives an overview of how the family and their substrates evolved from non-vertebrates to mammals, the expression of the hyalectanases and substrates in different species and their functions during development, and how these functions are conserved across species.