Versican Processing by a Disintegrin-like and Metalloproteinase Domain with Thrombospondin-1 Repeats Proteinases-5 and -15 Facilitates Myoblast Fusion

Abstract

Background: Skeletal muscle fiber formation requires myoblast cell-cell membrane contact and fusion. Results: A versican-rich pericellular matrix surrounding myoblasts is proteolytically cleared by ADAMTS versicanases facilitating myoblast contact and fusion. Conclusion: Versican processing by ADAMTS versicanases contribute to muscle fiber formation. Significance: Targeting versican remodeling could enhance the regenerative capacity of muscle by improving muscle fiber fusion during regeneration.

Biosynthesis and Expression of a Disintegrin-like and Metalloproteinase Domain with Thrombospondin-1 Repeats-15

“…This is in accordance with our recent study showing that ADAMTS15 could rescue an Adamts5-deficient myoblast fusion defect in an in vitro model of skeletal muscle fiber formation, mouse C2C12 cells (46). This study highlighted the expansion of a versican and hyaluronan-rich pericellular matrix surrounding myoblasts upon Adamts5 silencing, leading to the hypothesis that ADAMTS15 cooperates with ADAMTS5 to clear the pericellular matrix surrounding myoblasts during in vivo myogenesis, thus facilitating myoblast fusion and mature skeletal muscle fiber formation.…”

ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation

“…ADAMTS (A disintegrin-like and metalloprotease with thrombospondin type 1 motifs) proteinases (Apte, 2009) remodel provisional ECM in diverse morphogenetic processes (Dupuis et al, 2011; Enomoto, 2010; McCulloch et al, 2009; Stankunas et al, 2008; Stupka et al, 2013). ADAMTS9 is highly conserved; its C.elegans ortholog, Gon-1 is required for gonadal morphogenesis (Blelloch et al, 1999) and the D. melanogaster ortholog AdamTS-A is essential for salivary gland morphogenesis and germ cell migration (Ismat et al, 2013).…”

Hyaluronan Synthesis and Myogenesis

“…It has been speculated that it could be necessary to remove the hyaluronan-rich pericellular coat to allow myoblast fusion (16), presumably through allowing closer contact between cell membranes and associated proteins. This mechanism has been suggested recently as a method by which proteoglycan cleavage can prevent retention of an overwhelmingly large pericellular matrix and thus allow cell-cell contact and differentiation/fusion (57). Both Has2 knockdown and 4MU abolished the hyaluronidase-sensitive pericellular matrix and also inhibited myogenic differentiation.…”

“…Pericellular Exclusion Assay-The size of the pericellular matrix surrounding live C2C12 myoblasts was determined by a particle exclusion assay similar to that described previously (30,57). C2C12 myoblasts transfected to express GFP were seeded at a density of 5,000 cells/well in 6-well plates, and after 2 days of either 4-methylumbelliferone or Has2 siRNA, the assay was performed.…”