title: Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice.
abstract: Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx). Galgt2(-/-) mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Neha
authors.initials: N
authors.lastname: Singhal
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Yelda
authors.initials: Y
authors.lastname: Serinagaoglu
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Chandrasekharan
authors.affiliation: Department of Pediatrics, University of Kentucky College of Medicine, Kentucky Children's Hospital, Lexington, Kentucky.
authors.forename: Mandar
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Department of Pediatrics, University of Kentucky College of Medicine, Kentucky Children's Hospital, Lexington, Kentucky.
authors.forename: John A
authors.initials: JA
authors.lastname: Bauer
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Paulus M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio. Electronic address: paul.martin@nationwidechildrens.org.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Martin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency / Q000378:metabolism*; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009220:Myositis / Q000473:pathology; D015854:Up-Regulation
chemical_list: D016189:Dystrophin; D016695:Glycosyltransferases; C505903:Galgt2 protein, mouse