Submitted on August 26, 2005
Accepted on September 22, 2005
Pharmacological Rescue of the Dystrophin Complex in Duchenne and Becker Skeletal Muscle Explants by Proteasomal Inhibitor Treatment
Stefania Assereto1, Silvia Stringara1, Federica Sotgia2, Gloria Bonuccelli2, Aldo Broccolini3, Marina Pedemonte1, Monica Traverso1, Roberta Biancheri1, Federico Zara1, Claudio Bruno1, Michael P Lisanti2*, and Carlo Minetti1
1 Muscular and Neurodegenerative Disease Unit, Gaslini Pediatric Institute, Genoa, Italy
2 Muscular and Neurodegenerative Disease Unit, Gaslini Pediatric Institute, Genoa, Italy; Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
3 Neurological Unit, Catholic University, Rome, Italy
* To whom correspondence should be addressed. E-mail: lisanti{at}aecom.yu.edu.
In this report, we have developed a novel method to identify compounds that rescue the dystrophin glycoprotein complex in Duchenne and Becker muscular dystrophy patients. Briefly, freshly isolated skeletal muscle biopsies from affected patients (termed skeletal muscle explants) were maintained under defined cell culture conditions for a 24 hour period, in the absence or presence of a specific candidate compound. Using this approach, we show here that treatment with a well-characterized proteasomal inhibitor, namely MG-132, is sufficient to rescue the expression of dystrophin, 
-dystroglycan, and 
-sarcoglycan in skeletal muscle explants from Duchenne and Becker patients. These data are consistent with our previous findings employing the systemic treatment of a dystrophin-deficient mouse model (mdx mice), with MG-132 [Bonuccelli et al, 2003]. Our current results may have important new implications for the possible pharmacological treatment of muscular dystrophy in humans.
