title: Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment.
abstract: In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, beta-dystroglycan, and alpha-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663-1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in humans.
authors.affiliation: Muscular and Neurodegenerative Disease Unit, University of Genoa and G. Gaslini Pediatric Institute, Genoa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Assereto
authors.forename: Silvia
authors.initials: S
authors.lastname: Stringara
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Aldobrando
authors.initials: A
authors.lastname: Broccolini
authors.forename: Marina
authors.initials: M
authors.lastname: Pedemonte
authors.forename: Monica
authors.initials: M
authors.lastname: Traverso
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
mesh_terms: D000818:Animals; D001706:Biopsy; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D015853:Cysteine Proteinase Inhibitors; C483081:DAG1 protein, human; D016189:Dystrophin; D006023:Glycoproteins; D007976:Leupeptins; D046912:Multiprotein Complexes; D061988:Proteasome Inhibitors; D049031:Sarcoglycans; D049030:Dystroglycans; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde