Oxidative stress in Duchenne muscular dystrophy: Focus on the NRF2 redox pathway

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused bymutations in the dystrophin gene and characterized by progressive, lethalmuscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of amaster player of the anti-oxidant and anti-inflammatory response, namely NF-E2-related Factor 2, inmuscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed amodulation of relevantmarkers of the inflammatory response, such as heme oxygenase 1 and Inteleukin-6 (IL- 6), suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenicmousemodel, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophicmuscle observed in DMD patients. This study advances our understanding of the pathogenicmechanisms underlying DMD and defines the critical role of oxidative stress onmuscle wasting with clear implications for disease pathogenesis and therapy in human.