title: Proteasome inhibition improves the muscle of laminin α2 chain-deficient mice.
abstract: 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 dy(3K)/dy(3K) 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 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.
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden. virginie.carmignac@med.lu.se
authors.forename: Virginie
authors.initials: V
authors.lastname: Carmignac
authors.forename: Ronan
authors.initials: R
authors.lastname: Quéré
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007797:Laminin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000188:drug therapy*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics; D054875:Ubiquitination
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007797:Laminin; D007976:Leupeptins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C102645:laminin alpha 2; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde