title: Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and α7 integrin.
abstract: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin-glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of α7β1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of α7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan 'rescue' of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or α7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and α7β1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and α7β1 integrin.
authors.affiliation: Department of Integrative Biology and Physiology, Center for Duchenne Muscular Dystrophy.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Marshall
authors.affiliation: Department of Integrative Biology and Physiology, Center for Duchenne Muscular Dystrophy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oh
authors.affiliation: Department of Integrative Biology and Physiology, Center for Duchenne Muscular Dystrophy.
authors.forename: Eric
authors.initials: E
authors.lastname: Chou
authors.affiliation: Department of Integrative Biology and Physiology, Center for Duchenne Muscular Dystrophy.
authors.forename: Joy A
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Department of Integrative Biology and Physiology, Center for Duchenne Muscular Dystrophy.
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
authors.affiliation: Department of Pharmacology, Center for Molecular Medicine, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Burkin
authors.affiliation: Department of Integrative Biology and Physiology, Center for Duchenne Muscular Dystrophy, Molecular Biology Institute, Department of Neurology, University of California, Los Angeles, CA 90095, USA and rcrosbie@physci.ucla.edu.
authors.forename: Rachelle H
authors.initials: RH
authors.lastname: Crosbie-Watson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D049411:Utrophin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; D039001:Integrin alpha Chains; D016023:Integrins; D007797:Laminin; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C491632:Sspn protein, mouse; D049411:Utrophin; C085725:integrin alpha7; C082908:integrin alpha7beta1