Elucidation of pathomechanism of and development of therapy ofautophagy-related muscle disorders

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To elucidate the pathomechanism of and to develop the therapy of autophagy-related muscle disorders, we physiologically and pathologically characterized the phenotypes of skeletal and cardiac muscles from Lamp-2 knock-out mice, a model mouse for Danon disease, and analyzed the recovery of phenotype by exogenous expression of the Lamp-2 homolog, Lamp-1. By cross-mating with Lamp-1 overexpressing mouse, cardiac functions was recovered in Lamp-2 knock-out mice. In Lamp-2 deficient cells, degradation by macroautophagy was remarkably decreased. This decrease was corrected by Lamp-1 overexpression. Most likely, Lamp-1 overexpression improves the fusion between autophagosomes and lysosomes, and ameliorates the cell dysfunction caused by Lamp-2 deficiency. Overall, induction of Lamp-1 expression may be a good candidate for the development of therapy for Danon disease.