Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment.
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.
Assereto
Stefania
S
Muscular and Neurodegenerative Disease Unit, University of Genoa and G. Gaslini Pediatric Institute, Genoa, Italy.
Stringara
Silvia
S
Sotgia
Federica
F
Bonuccelli
Gloria
G
Broccolini
Aldobrando
A
Pedemonte
Marina
M
Traverso
Monica
M
Biancheri
Roberta
R
Zara
Federico
F
Bruno
Claudio
C
Lisanti
Michael P
MP
Minetti
Carlo
C
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
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