title: Muscle-specific expression of LARGE restores neuromuscular transmission deficits in dystrophic LARGE(myd) mice.
abstract: Mutations in several glycosyltransferases underlie a group of muscular dystrophies known as glycosylation-deficient muscular dystrophy. A common feature of these diseases is loss of glycosylation and consequent dystroglycan function that is correlated with severe pathology in muscle, brain and other tissues. Although glycosylation of dystroglycan is essential for function in skeletal muscle, whether glycosylation-dependent function of dystroglycan is sufficient to explain all complex pathological features associated with these diseases is less clear. Dystroglycan glycosylation is defective in LARGE(myd) (myd) mice as a result of a mutation in like-acetylglucosaminyltransferase (LARGE), a glycosyltransferase known to cause muscle disease in humans. We generated animals with restored dystroglycan function exclusively in skeletal muscle by crossing myd animals to a recently created transgenic line that expresses LARGE selectively in differentiated muscle. Transgenic myd mice were indistinguishable from wild-type littermates and demonstrated an amelioration of muscle disease as evidenced by an absence of muscle pathology, restored contractile function and a reduction in serum creatine kinase activity. Moreover, although deficits in nerve conduction and neuromuscular transmission were observed in myd animals, these deficits were fully rescued by muscle-specific expression of LARGE, which resulted in restored structure of the neuromuscular junction (NMJ). These data demonstrate that, in addition to muscle degeneration and dystrophy, impaired neuromuscular transmission contributes to muscle weakness in dystrophic myd mice and that the noted defects are primarily due to the effects of LARGE and glycosylated dystroglycan in stabilizing the endplate of the NMJ.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Gumerson
authors.forename: Carol S
authors.initials: CS
authors.lastname: Davis
authors.forename: Zhyldyz T
authors.initials: ZT
authors.lastname: Kabaeva
authors.forename: John M
authors.initials: JM
authors.lastname: Hayes
authors.forename: Susan V
authors.initials: SV
authors.lastname: Brooks
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
mesh_terms: D000818:Animals; D049030:Dystroglycans / Q000378:metabolism; D006031:Glycosylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009048:Motor Skills; D018482:Muscle, Skeletal / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009928:Organ Specificity; D011499:Protein Processing, Post-Translational; D009435:Synaptic Transmission
chemical_list: D049030:Dystroglycans; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases