title: Heparan sulfate 6-O-endosulfatases (Sulfs) coordinate the Wnt signaling pathways to regulate myoblast fusion during skeletal muscle regeneration.
abstract: Skeletal muscle regeneration is mediated by satellite cells (SCs). Upon injury, SCs undergo self-renewal, proliferation, and differentiation into myoblasts followed by myoblast fusion to form new myofibers. We previously showed that the heparan sulfate (HS) 6-O-endosulfatases (Sulf1 and -2) repress FGF signaling to induce SC differentiation during muscle regeneration. Here, we identify a novel role of Sulfs in myoblast fusion using a skeletal muscle-specific Sulf double null (Sulf(SK)-DN) mouse. Regenerating Sulf(SK)-DN muscles exhibit reduced canonical Wnt signaling and elevated non-canonical Wnt signaling. In addition, we show that Sulfs are required to repress non-canonical Wnt signaling to promote myoblast fusion. Notably, skeletal muscle-relevant non-canonical Wnt ligands lack HS binding capacity, suggesting that Sulfs indirectly repress this pathway. Mechanistically, we show that Sulfs reduce the canonical Wnt-HS binding and regulate colocalization of the co-receptor LRP5 with caveolin3. Therefore, Sulfs may increase the bioavailability of canonical Wnts for Frizzled receptor and LRP5/6 interaction in lipid raft, which may in turn antagonize non-canonical Wnt signaling. Furthermore, changes in subcellular distribution of active focal adhesion kinase (FAK) are associated with the fusion defect of Sulf-deficient myoblasts and upon non-canonical Wnt treatment. Together, our findings uncover a critical role of Sulfs in myoblast fusion by promoting antagonizing canonical Wnt signaling activities against the noncanonical Wnt pathway during skeletal muscle regeneration.
authors.affiliation: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Tran
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Shi
authors.forename: Joseph
authors.initials: J
authors.lastname: Zaia
authors.forename: Xingbin
authors.initials: X
authors.lastname: Ai
mesh_terms: D000818:Animals; D002459:Cell Fusion; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000201:enzymology*; D012038:Regeneration / Q000502:physiology*; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D006497:Heparan Sulfate; D013429:Sulfatases; D015238:Sulfotransferases; D051153:Wnt Proteins; C486773:Sulf1 protein, mouse; C514911:Sulf2 protein, mouse