STUDY OF OXIDATIVE STRESS AND ANTIOXIDANT RESPONSE IN THE SGCA NULL DYSTROPHIC MOUSE MODEL

During my PhD, I mainly focus on the of dietary antioxidant and the role of oxidative stress in the progression of Muscular Dystrophy (MDs). MDs are genetic human diseases which are hallmarked by a progressive muscle wasting of variable severity, in the most severe cases this condition leads patients to wheelchair life and premature death due to respiratory and cardiac failure (Emery 2002). Mutations, in these pathologies, mainly affect the Dystrophin-associated Glycoprotein Complex (DGC); this multiprotein complex is located in the myofiber sarcolemma and links the fibers to the extracellular matrix conferring stability to fiber structure. The absence or the malfunction of the DGC leads to myofibers instability, which leads to fibers death and in time compromise muscle functionality. In the most severe cases MD patients would die of respiratory and cardiac failure. Nowadays there is no definitive treatment for MDs that can cure the root of the pathology, although among the different approaches, many efforts are directed to slow down the progression of the disease to counteract the progressive degeneration and to improve patients life quality (Cossu & Sampaolesi 2007). It is now very well established that the DGC not only plays a structural role for the myofiber stability, but also its stretch during contraction is essential for the activation of important signalling pathways. In fact, in literature is known that accumulation of reactive oxygen species (ROS) and oxidative stress contribute strongly to the worsening of MDs, suggesting that muscles affected by these diseases display an impairment in antioxidant signalling (Rando 1998; Rando 2002). In this study, we show that an cyanidin enriched diet is able to delay MD progression in the dystrophic mouse model Sgca null. In particular we display a morphological amelioration of muscle tissue organization, more fiber stability and rescue of muscle performance. Moreover, the antioxidant diet is able to interfere with the proinflammatory environment, typical of these pathologies. Specifically, cyanidin impairs NF-kB translocation into the myonuclei, and prevent the expression of typical pro-inflammatory genes such as TNF- and iNOS. Furthermore, we observe an increase of the antioxidant response in dystrophic mice fed with this particular diet. We found that the transcriptional levels of antioxidant genes (i.e. HO-1 and GCLC), in this scenario, are increased through the activity a specific transcription factor known as Nrf-2. We investigate on the signalling pathway that promote Nrf-2 nuclei localization, finding that AMPK activity is the crucial factor.