title: Dystrophin insufficiency causes selective muscle histopathology and loss of dystrophin-glycoprotein complex assembly in pig skeletal muscle.
abstract: The purpose of this investigation was to determine the extent to which dystrophin insufficiency caused histomorphological changes in a novel pig model of Becker muscular dystrophy. In our procedures, we used a combination of biochemical approaches, including quantitative PCR and Western blots, along with a histological analysis using standard and immunohistological measures. We found that 8-wk-old male affected pigs had a 70% reduction in dystrophin protein abundance in the diaphragm, psoas major, and longissimus lumborum and a 5-fold increase in serum creatine kinase activity compared with healthy male littermates. Dystrophin insufficiency in the diaphragm and the longissimus resulted in muscle histopathology with disorganized fibrosis that often colocalized with fatty infiltration but not the psoas. Affected animals also had an 80-85% reduction in α-sarcoglycan localization in these muscles, indicating compromised assembly of the dystrophin glycoprotein complex. Controls used in this study were 4 healthy male littermates, as they are most closely related to the affected animals. We concluded that pigs with insufficient dystrophin protein expression have a phenotype consistent with human dystrophinopathy patients. Given that and their similarity in body size and physiology to humans, we further conclude that this pig line is an appropriate translational model for dystrophinopathies.
authors.affiliation: 1Iowa State University, Department of Animal Science, 2356 Kildee Hall, Ames, IA 50011, USA. jselsby@iastate.edu.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hollinger
authors.forename: Cai X
authors.initials: CX
authors.lastname: Yang
authors.forename: Robyn E
authors.initials: RE
authors.lastname: Montz
authors.forename: Dan
authors.initials: D
authors.lastname: Nonneman
authors.forename: Jason W
authors.initials: JW
authors.lastname: Ross
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Selsby
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D003402:Creatine Kinase / Q000097:blood; D003964:Diaphragm / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049031:Sarcoglycans / Q000378:metabolism; D013552:Swine
chemical_list: D016189:Dystrophin; D006023:Glycoproteins; D049031:Sarcoglycans; D003402:Creatine Kinase
keywords: BMD; Becker muscular dystrophy; DMD; Duchenne muscular dystrophy; animal model