| First Author | Carmignac V | Year | 2011 |
| Journal | Hum Mol Genet | Volume | 20 |
| Issue | 3 | Pages | 541-52 |
| PubMed ID | 21084425 | Mgi Jnum | J:167230 |
| Mgi Id | MGI:4867586 | Doi | 10.1093/hmg/ddq499 |
| Citation | Carmignac V, et al. (2011) Proteasome inhibition improves the muscle of laminin {alpha}2 chain-deficient mice. Hum Mol Genet 20(3):541-52 |
| abstractText | Muscle atrophy, a significant characteristic of congenital muscular dystrophy with laminin alpha2 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 dy(3K)/dy(3K) mutant mouse model of MDC1A, we studied the expression of members of the ubiquitin-proteasome pathway in laminin alpha2 chain-deficient muscle, and we treated dy(3K)/dy(3K) 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 dy(3K)/dy(3K) 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. |
