T.P.40 Implication of SIRT1 and its downstream pathways in dystrophic process

Abstract Muscle necrosis and exhaustible muscle regeneration are key elements in Duchenne muscular dystrophy (DMD) pathogenesis. Our group has previously highlighted the detrimental effects of the cross-talk between oxidative stress, lipid peroxidation and NF-kappaB/TNF-α activation in the necrotic process in DMD and its murine model. The positive effects of their pharmacological inhibition on muscle regeneration were also demonstrated. Moreover the contribution of telomere shortening to the depletion of regenerative spurt is an emerging field of investigation. SIRT1, an enzyme belonging to the deacetylase family of sirtuins, inhibits NF-kappaB/TNF-α inflammatory pathway. SIRT 1 role in muscle regeneration is still controversial: it promotes telomere maintenance and muscle cell proliferation mediating IGF1 effect. On the other hand, it inhibits mTOR pathway, known to mediate skeletal muscle regeneration and remodeling. This evidence has been provided only by in vitro and in vivo studies and administration of resveratrol, a SIRT 1 activator, ameliorated muscle pathology in mdx mice. This study aimed to investigate the expression of SIRT1, NF-kappaB, IGF1-Akt/PKB and mTOR pathways in dystrophic patient muscles. Muscles of DMD, facioscapulohumeral (FSH) and limb-girdle muscular dystrophies (LGMD) and controls were examined by immunohistochemistry Western blot and real-time PCR. The above mentioned factors have been found overexpressed in DMD and LGMD, at variance with FSH. Moreover SIRT 1 was specifically expressed at immunohistochemistry by miogenin-positive satellite cells. The understanding of the mechanisms controlling SIRT1 and downstream pathways in muscle dystrophies could provide clues in identifying novel therapeutic targets.