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Autophagy is increased in laminin {alpha}2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A.

Carmignac, Virginie LU ; Svensson, Martina; Körner, Zandra; Elowsson, Linda LU ; Matsumura, Cintia LU ; Gawlik, Kinga LU ; Allamand, Valerie and Durbeej-Hjalt, Madeleine LU (2011) In Human Molecular Genetics 20(24). p.4891-4902
Abstract
Congenital muscular dystrophy caused by laminin α2 chain deficiency (also known as MDC1A) is a severe and incapacitating disease, characterized by massive muscle wasting. The ubiquitin-proteasome system plays a major role in muscle wasting and we recently demonstrated that increased proteasomal activity is a feature of MDC1A. The autophagy-lysosome pathway is the other major system involved in degradation of proteins and organelles within the muscle cell. However, it remains to be determined if the autophagy-lysosome pathway is dysregulated in muscular dystrophies, including MDC1A. Using the dy(3K)/dy(3K) mouse model of laminin α2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is... (More)
Congenital muscular dystrophy caused by laminin α2 chain deficiency (also known as MDC1A) is a severe and incapacitating disease, characterized by massive muscle wasting. The ubiquitin-proteasome system plays a major role in muscle wasting and we recently demonstrated that increased proteasomal activity is a feature of MDC1A. The autophagy-lysosome pathway is the other major system involved in degradation of proteins and organelles within the muscle cell. However, it remains to be determined if the autophagy-lysosome pathway is dysregulated in muscular dystrophies, including MDC1A. Using the dy(3K)/dy(3K) mouse model of laminin α2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is upregulated in laminin α2 chain-deficient muscle. Moreover, we found that autophagy inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. In particular, we show that systemic injection of 3-methyladenine (3-MA) reduces muscle fibrosis, atrophy, apoptosis and increases muscle regeneration and muscle mass. Importantly, lifespan and locomotive behavior were also greatly improved. These findings indicate that enhanced autophagic activity is pathogenic and that autophagy inhibition holds a promising therapeutic potential in the treatment of MDC1A. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
20
issue
24
pages
4891 - 4902
publisher
Oxford University Press
external identifiers
  • wos:000297242100012
  • pmid:21920942
  • scopus:81855205301
ISSN
0964-6906
DOI
10.1093/hmg/ddr427
language
English
LU publication?
yes
id
09f80206-2e52-43e2-98b6-1baf0c40d912 (old id 2168487)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21920942?dopt=Abstract
date added to LUP
2011-10-03 13:56:05
date last changed
2017-10-01 03:14:13
@article{09f80206-2e52-43e2-98b6-1baf0c40d912,
  abstract     = {Congenital muscular dystrophy caused by laminin α2 chain deficiency (also known as MDC1A) is a severe and incapacitating disease, characterized by massive muscle wasting. The ubiquitin-proteasome system plays a major role in muscle wasting and we recently demonstrated that increased proteasomal activity is a feature of MDC1A. The autophagy-lysosome pathway is the other major system involved in degradation of proteins and organelles within the muscle cell. However, it remains to be determined if the autophagy-lysosome pathway is dysregulated in muscular dystrophies, including MDC1A. Using the dy(3K)/dy(3K) mouse model of laminin α2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is upregulated in laminin α2 chain-deficient muscle. Moreover, we found that autophagy inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. In particular, we show that systemic injection of 3-methyladenine (3-MA) reduces muscle fibrosis, atrophy, apoptosis and increases muscle regeneration and muscle mass. Importantly, lifespan and locomotive behavior were also greatly improved. These findings indicate that enhanced autophagic activity is pathogenic and that autophagy inhibition holds a promising therapeutic potential in the treatment of MDC1A.},
  author       = {Carmignac, Virginie and Svensson, Martina and Körner, Zandra and Elowsson, Linda and Matsumura, Cintia and Gawlik, Kinga and Allamand, Valerie and Durbeej-Hjalt, Madeleine},
  issn         = {0964-6906},
  language     = {eng},
  number       = {24},
  pages        = {4891--4902},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Autophagy is increased in laminin {alpha}2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A.},
  url          = {http://dx.doi.org/10.1093/hmg/ddr427},
  volume       = {20},
  year         = {2011},
}