title: Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.
abstract: Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Körner
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Cibely C
authors.initials: CC
authors.lastname: Fontes-Oliveira
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
authors.affiliation: Genetics of Developmental Abnormalities Team, EA4271, University of Burgundy, Dijon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Carmignac
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. Electronic address: madeleine.durbeej-hjalt@med.lu.se.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D000069286:Bortezomib; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D007797:Laminin / Q000172:deficiency* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D001897:Boronic Acids; D007797:Laminin; D035683:MicroRNAs; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex