Research on the elucidation of molecular pathomechanism of and the development of therapy of lysosomal muscle diseases.

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We group lysosomal muscle disease into autophagic vacuolar myopathy (AVM) and rimmed vacuolar myopathy (RVM).For AVM, we focused on developing a therapy for Danon disease (primary LAMP・deficiency) by overexpressing LAMP・, a homolog of LAMP・. We first evaluated the physiological performance of skeletal muscle of LAMP・knockout (KO) mice. Although their maximum motor performance did not statistically differ from controls, their endurance was much lower. Analysis of isolated muscles showed that the contractile force similar to control. Pathologically, autophagic vacuoles were prominent in muscle fibers, as seen in human patients. We next generated LAMP-1 transgenic (Tg) mice. LAMP-1 Tg mice were born normally and did not show any phenotype. We cross-mated LAMP-2KO and LAMP・Tg mice and successfully obtained LAMP2 KO mice overexpressing LAMP-1. These mice showed better endurance than LAMP・KO mice, strongly suggesting that LAMP-1 overexpression may compensate for the phenotype, at least in skeletal muscle.For RVM, we evaluated the lysosomal abnormalities in distal myopathies with rimmed vacuoles (DMRV). DMRV is an autosomal recessive disease pathologically characterized by rimmed vacuoles and amyloid deposition on light microscopy, and tubulofilamentous inclusion bodies on electron microscopy. The disease is caused by missense mutations in GNE gene. We recently established DMRV model mice which lacked their own GNEbut expressed human GNEwith V572L mutation, which is the most common mutation among Japanese DMRV patients. We investigated the pathomechanism of DMRV focusing on autophagy and amyloid deposition in the skeletal muscles using our DMRV mice. Amyloid deposition preceded rimmed vacuole formation, indicating that amyoloid is depeosited prior to autophagic process. In addition, these lysosomal accumulations were seen mainly in type 2B fibers. This pattern was similar to that seen in LAMP・KO mouse, suggesting a common pathomechamism between RVM and AVM.