title: Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex.
abstract: Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of (gamma)- and (delta)-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.
authors.affiliation: Department of Molecular Genetics and Cell Biology, Section of Cardiology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Hack
authors.forename: M Y
authors.initials: MY
authors.lastname: Lam
authors.forename: L
authors.initials: L
authors.lastname: Cordier
authors.forename: D I
authors.initials: DI
authors.lastname: Shoturma
authors.forename: C T
authors.initials: CT
authors.lastname: Ly
authors.forename: M A
authors.initials: MA
authors.lastname: Hadhazy
authors.forename: M R
authors.initials: MR
authors.lastname: Hadhazy
authors.forename: H L
authors.initials: HL
authors.lastname: Sweeney
authors.forename: E M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology*; D002463:Cell Membrane Permeability; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D018390:Gene Targeting; D006031:Glycosylation; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout / Q000235:genetics; D008954:Models, Biological; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D020836:Protein Structure, Quaternary / Q000235:genetics; D049031:Sarcoglycans
chemical_list: D003598:Cytoskeletal Proteins; D016189:Dystrophin; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D049031:Sarcoglycans