Journal Article

Proteasome inhibition improves the muscle of laminin α2 chain-deficient mice

Virginie Carmignac, Ronan Quéré and Madeleine Durbeej

in Human Molecular Genetics

Volume 20, issue 3, pages 541-552
Published in print February 2011 | ISSN: 0964-6906
Published online November 2010 | e-ISSN: 1460-2083 | DOI:
Proteasome inhibition improves the muscle of laminin α2 chain-deficient mice

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Muscle atrophy, a significant characteristic of congenital muscular dystrophy with laminin α2 chain deficiency (also known as MDC1A), occurs by a change in the normal balance between protein synthesis and protein degradation. The ubiquitin–proteasome system (UPS) plays a key role in protein degradation in skeletal muscle cells. In order to identify new targets for drug therapy against MDC1A, we have investigated whether increased proteasomal degradation is a feature of MDC1A. Using the generated dy3K/dy3K mutant mouse model of MDC1A, we studied the expression of members of the ubiquitin–proteasome pathway in laminin α2 chain-deficient muscle, and we treated dy3K/dy3K mice with the proteasome inhibitor MG-132. We show that members of the UPS are upregulated and that the global ubiquitination of proteins is raised in dystrophic limb muscles. Also, phosphorylation of Akt is diminished in diseased muscles. Importantly, proteasome inhibition significantly improves the dystrophic dy3K/dy3K phenotype. Specifically, treatment with MG-132 increases lifespan, enhances locomotive activity, enlarges muscle fiber diameter, reduces fibrosis, restores Akt phosphorylation and decreases apoptosis. These studies promote better understanding of the disease process in mice and could lead to a drug therapy for MDC1A patients.

Journal Article.  5990 words.  Illustrated.

Subjects: Genetics and Genomics

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