Bortezomib Partially Improves Laminin α2 Chain-Deficient Muscular Dystrophy.
(2014) In American Journal of Pathology 184(5). p.1518-1528- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4383212
- author
- Körner, Zandra LU ; Fontes Oliveira, Cibely LU ; Holmberg, Johan K LU ; Carmignac, Virginie LU and Durbeej-Hjalt, Madeleine LU
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- American Journal of Pathology
- volume
- 184
- issue
- 5
- pages
- 1518 - 1528
- publisher
- American Society for Investigative Pathology
- external identifiers
-
- pmid:24631023
- wos:000335284400025
- scopus:84899502670
- pmid:24631023
- ISSN
- 1525-2191
- DOI
- 10.1016/j.ajpath.2014.01.019
- language
- English
- LU publication?
- yes
- id
- 5bf98dad-6b2e-4673-8af2-be0573e0acba (old id 4383212)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24631023?dopt=Abstract
- date added to LUP
- 2016-04-01 10:38:32
- date last changed
- 2022-04-20 04:50:47
@article{5bf98dad-6b2e-4673-8af2-be0573e0acba,
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.}},
author = {{Körner, Zandra and Fontes Oliveira, Cibely and Holmberg, Johan K and Carmignac, Virginie and Durbeej-Hjalt, Madeleine}},
issn = {{1525-2191}},
language = {{eng}},
number = {{5}},
pages = {{1518--1528}},
publisher = {{American Society for Investigative Pathology}},
series = {{American Journal of Pathology}},
title = {{Bortezomib Partially Improves Laminin α2 Chain-Deficient Muscular Dystrophy.}},
url = {{http://dx.doi.org/10.1016/j.ajpath.2014.01.019}},
doi = {{10.1016/j.ajpath.2014.01.019}},
volume = {{184}},
year = {{2014}},
}