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Dev Biol. 2014 Sep 15;393(2):298-311. doi: 10.1016/j.ydbio.2014.06.025. Epub 2014 Jul 11.

GRAF1 promotes ferlin-dependent myoblast fusion.

Author information

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
Department of Pathology and Laboratory, Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Department of Pathology and Laboratory, Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jmt3x@med.unc.edu.

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.

KEYWORDS:

Endocytic recycling; Ferlin; GRAF; Myoblast fusion

PMID:
25019370
PMCID:
PMC4535172
DOI:
10.1016/j.ydbio.2014.06.025
[Indexed for MEDLINE]
Free PMC Article

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