title: Constitutive properties, not molecular adaptations, mediate extraocular muscle sparing in dystrophic mdx mice.
abstract: Extraocular muscle (EOM) is spared in Duchenne muscular dystrophy. Here, we tested putative EOM sparing mechanisms predicted from existing dystrophinopathy models. Data show that mdx mouse EOM contains dystrophin-glycoprotein complex (DGC)-competent and DGC-deficient myofibers distributed in a fiber type-specific pattern. Up-regulation of a dystrophin homologue, utrophin, mediates selective DGC retention. Counter to the DGC mechanical hypothesis, an intact DGC is not a precondition for EOM sarcolemmal integrity, and active adaptation at the level of calcium homeostasis is not mechanistic in protection. A partial, fiber type-specific retention of antiischemic nitric oxide to vascular smooth muscle signaling is not a factor in EOM sparing, because mice deficient in dystrophin and alpha-syntrophin, which localizes neuronal nitric oxide synthase to the sarcolemma, have normal EOMs. Moreover, an alternative transmembrane protein, alpha7beta1 integrin, does not appear to substitute for the DGC in EOM. Finally, genomewide expression profiling showed that EOM does not actively adapt to dystrophinopathy but identified candidate genes for the constitutive protection of mdx EOM. Taken together, data emphasize the conditional nature of dystrophinopathy and the potential importance of nonmechanical DGC roles and support the hypothesis that broad, constitutive structural cell signaling, and/or biochemical differences between EOM and other skeletal muscles are determinants of differential disease responsiveness.
authors.affiliation: Department of Ophthalmology, Case Western Reserve University and The Research Institute of University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, Ohio 44106-5068, USA. jdp7@po.cwru.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Porter
authors.forename: Anita P
authors.initials: AP
authors.lastname: Merriam
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Khanna
authors.forename: Francisco H
authors.initials: FH
authors.lastname: Andrade
authors.forename: Chelliah R
authors.initials: CR
authors.lastname: Richmonds
authors.forename: Patrick
authors.initials: P
authors.lastname: Leahy
authors.forename: Georgiana
authors.initials: G
authors.lastname: Cheng
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Karathanasis
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhou
authors.forename: Linda L
authors.initials: LL
authors.lastname: Kusner
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Adams
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mayer
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaminski
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins; D016000:Cluster Analysis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency / Q000378:metabolism; D015870:Gene Expression; D006487:Hemostasis; D007150:Immunohistochemistry; D039001:Integrin alpha Chains / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D009801:Oculomotor Muscles / Q000378:metabolism* / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D012508:Sarcolemma / Q000378:metabolism; D049411:Utrophin
chemical_list: D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D039001:Integrin alpha Chains; D008565:Membrane Proteins; D009124:Muscle Proteins; C483600:Utrn protein, mouse; D049411:Utrophin; C085725:integrin alpha7; C091825:syntrophin alpha1; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D002118:Calcium