Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice.
Recent studies have shown that a number of genes that are not mutated in various forms of muscular dystrophy may serve as surrogates to protect skeletal myofibers from injury. One such gene is Galgt2, which is also called cytotoxic T cell GalNAc transferase in mice. In this study, we show that Galgt2 overexpression reduces the development of dystrophic pathology in the skeletal muscles of mice lacking alpha sarcoglycan (Sgca), a mouse model for limb girdle muscular dystrophy 2D. Galgt2 transgenic Sgca(-/-) mice showed reduced levels of myofiber damage, as evidenced by i) normal levels of serum creatine kinase activity, ii) a lack of Evans blue dye uptake into myofibers, iii) normal levels of mouse locomotor activity, and iv) near normal percentages of myofibers with centrally located nuclei. In addition, the overexpression of Galgt2 in the early postnatal period using an adeno-associated virus gene therapy vector protected Sgca(-/-) myofibers from damage, as observed using histopathology measurements. Galgt2 transgenic Sgca(-/-) mice also had increased levels of glycosylation of alpha dystroglycan with the CT carbohydrate, but showed no up-regulation of beta, gamma, delta, or epsilon sarcoglycan. These data, coupled with results from our previous studies, show that Galgt2 has therapeutic effects in three distinct forms of muscular dystrophy and may, therefore, have a broad spectrum of therapeutic potential for the treatment of various myopathies.
Xu
Rui
R
the Departments of Pediatrics, Center for Gene Therapy, Physiology and Cell Biology, Ohio State University College of Medicine, Columbus, Ohio 43205, USA.
DeVries
Sarah
S
Camboni
Marybeth
M
Martin
Paul T
PT
D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016133:Polymerase Chain Reaction; D049031:Sarcoglycans / Q000172:deficiency* / Q000235:genetics
D049031:Sarcoglycans; D016695:Glycosyltransferases; C505903:Galgt2 protein, mouse