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Proteasome Inhibition Improves the Muscle of Laminin {alpha}2 Chain Deficient Mice.

Carmignac, Virginie LU ; Quere, Ronan LU and Durbeej-Hjalt, Madeleine LU (2011) In Human Molecular Genetics 20(3). p.541-552
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 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... (More)
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 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 ubiquitin-proteasome system 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
20
issue
3
pages
541 - 552
publisher
Oxford University Press
external identifiers
  • wos:000286006300012
  • pmid:21084425
  • scopus:78651076693
ISSN
0964-6906
DOI
10.1093/hmg/ddq499
language
English
LU publication?
yes
id
99e50975-5937-443b-a398-649a478caa17 (old id 1731851)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21084425?dopt=Abstract
date added to LUP
2010-12-01 12:13:56
date last changed
2017-10-01 03:01:17
@article{99e50975-5937-443b-a398-649a478caa17,
  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 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 ubiquitin-proteasome system 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.},
  author       = {Carmignac, Virginie and Quere, Ronan and Durbeej-Hjalt, Madeleine},
  issn         = {0964-6906},
  language     = {eng},
  number       = {3},
  pages        = {541--552},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Proteasome Inhibition Improves the Muscle of Laminin {alpha}2 Chain Deficient Mice.},
  url          = {http://dx.doi.org/10.1093/hmg/ddq499},
  volume       = {20},
  year         = {2011},
}