Targeting RAGE as a potential therapeutic approach to Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease affecting striated muscles, which undergo progressive degeneration and chronic inflammation. Receptor for advanced glycation end-products (RAGE), a multiligand receptor involved in myogenesis and inflammation, is absent in healthy adult muscles but is re-expressed in myoblasts, regenerating myofibers and activated immune cells upon acute muscle injury, and in certain myopathies. We show here that RAGE is expressed and chronically stimulated in muscles of mdx mice, an experimental model of DMD, which also release high amounts of the RAGE ligands, HMGB1 and S100B. We generated a double mutant, mdx/Ager(-/-) mouse lacking dystrophin and RAGE. Compared to mdx mice, muscles of mdx/Ager(-/-) mice show restrained inflammation, unaffected fibrosis and higher muscle strength. Mdx/Ager(-/-) macrophages are less responsive to proinflammatory stimuli and express lower levels of Ccr2, Ccl2 and Ccl7, which are involved in monocyte/macrophage chemotaxis and migration. In vivo treatment of dystrophic muscles with a RAGE blocking antibody results in reduced necrosis and inflammatory infiltrate. Our results suggest that RAGE sustains muscle inflammation and necrosis in DMD muscles and that reducing RAGE activity might represent a potential therapeutic tool to counteract muscle inflammation and rescue muscle morphology in DMD conditions.