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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenine / administration & dosage
-
Adenine / analogs & derivatives
-
Adenine / pharmacology
-
Adenine / therapeutic use
-
Animals
-
Apoptosis / drug effects
-
Autophagy* / drug effects
-
Autophagy* / genetics
-
Behavior, Animal / drug effects
-
Disease Models, Animal
-
Drug Therapy, Combination
-
Fibrosis
-
Gene Expression Regulation
-
Injections
-
Laminin / antagonists & inhibitors*
-
Laminin / deficiency*
-
Laminin / metabolism
-
Leupeptins / pharmacology
-
Leupeptins / therapeutic use
-
Mice
-
Motor Activity / drug effects
-
Muscles / metabolism
-
Muscles / pathology*
-
Muscles / physiopathology
-
Muscular Atrophy / complications
-
Muscular Atrophy / drug therapy
-
Muscular Atrophy / pathology
-
Muscular Atrophy / physiopathology
-
Muscular Dystrophies / complications
-
Muscular Dystrophies / drug therapy
-
Muscular Dystrophies / pathology*
-
Muscular Dystrophies / physiopathology
-
Peripheral Nervous System Diseases / complications
-
Peripheral Nervous System Diseases / drug therapy
-
Peripheral Nervous System Diseases / pathology
-
Peripheral Nervous System Diseases / physiopathology
-
Phenotype
-
Phosphorylation / drug effects
-
Proto-Oncogene Proteins c-akt / metabolism
-
Regeneration
-
Survival Analysis
Substances
-
Laminin
-
Leupeptins
-
laminin alpha 2
-
3-methyladenine
-
Proto-Oncogene Proteins c-akt
-
Adenine
-
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Supplementary concepts
-
Muscular dystrophy congenital, merosin negative