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

作者：Carmignac Virginie^*; Svensson Martina; Korner Zandra; Elowsson Linda; Matsumura Cintia; Gawlik Kinga I; Allamand Valerie; Durbeej Madeleine

来源：Human Molecular Genetics, 2011, 20(24): 4891-4902.

DOI：10.1093/hmg/ddr427

Congenital muscular dystrophy caused by laminin alpha 2 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 alpha 2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is upregulated in laminin alpha 2 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.

• 出版日期2011-12-15