GRAF1 promotes ferlin-dependent myoblast fusion |
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Authors: | Kaitlin C. Lenhart Abby L. Becherer Jianbin Li Xiao Xiao Elizabeth M. McNally Christopher P. Mack Joan M. Taylor |
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Affiliation: | 1. Department of Pathology and Laboratory, Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA;2. Department of Gene Therapy Molecular Pharmaceutics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA;3. Department of Medicine, The University of Chicago, Chicago, IL, USA;4. McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA |
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Abstract: | Myoblast fusion (a critical process by which muscles grow) occurs in a multi-step fashion that requires actin and membrane remodeling; but important questions remain regarding the spatial/temporal regulation of and interrelationship between these processes. We recently reported that the Rho-GAP, GRAF1, was particularly abundant in muscles undergoing fusion to form multinucleated fibers and that enforced expression of GRAF1 in cultured myoblasts induced robust fusion by a process that required GAP-dependent actin remodeling and BAR domain-dependent membrane sculpting. Herein we developed a novel line of GRAF1-deficient mice to explore a role for this protein in the formation/maturation of myotubes in vivo. Post-natal muscles from GRAF1-depleted mice exhibited a significant and persistent reduction in cross-sectional area, impaired regenerative capacity and a significant decrease in force production indicative of lack of efficient myoblast fusion. A significant fusion defect was recapitulated in isolated myoblasts depleted of GRAF1 or its closely related family member GRAF2. Mechanistically, we show that GRAF1 and 2 facilitate myoblast fusion, at least in part, by promoting vesicle-mediated translocation of fusogenic ferlin proteins to the plasma membrane. |
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Keywords: | GRAF Endocytic recycling Ferlin Myoblast fusion |
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