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

Abstract

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NF-E2-related Factor 2, in muscle 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 a modulation of relevant markers 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 transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human.

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

“…In contrast, the progressive increase of NOX2 expression in symptomatic DMD patients (2-9 years of age) failed to activate the Nrf2-mediated antioxidant response [77]. These data strongly indicate that the imbalance between oxidant and antioxidant systems is involved in DMD progression [78,[80][81][82].…”

“…We recently reported the existence of an antioxidant compensatory mechanism in muscles of young mdx mice and human patients before the onset of DMD symptoms (0-2 years). In particular, we observed a significant upregulation of several Nrf2-dependent genes and enzymes to counteract the strong induction of NOX2 (NADPH oxidase 2) expression, the major source of ROS production in dystrophic muscles [77,79].…”

“…Indeed, the induction of Nrf2, by the Nrf2 activator sulforaphane (SFN), was shown to reduce muscle inflammation and fibrosis in dystrophic mice, thereby improving muscle function [74][75][76]. The central role of the Nrf2 pathway in DMD pathophysiology is further supported by clinical studies in which the expression of Nrf2 was found to be upregulated in very young DMD patients early before the appearance of symptoms but not during the progression of disease, when the severity of muscular dystrophy is clearly observed [77].…”

“…Moreover, the enhanced ROS production induced by increased levels of the pro-inflammatory cytokine IL-6 in mdx mice was also related to an altered redox status of dystrophic muscle due to the impinged Nrf2-mediated anti-oxidant response, closely approximating DMD progression in human patients [77,79].…”

Systemic Activation of Nrf2 Pathway in Parkinson's Disease

“…In 32 PD and 32 CTL samples, blood Reduced Glutathione/Oxidized Glutathione (GSH/GSSG) levels, mitochondrial complex I (CI) and citrate synthase (CS) enzyme activity were assessed by enzymatic recycling, MitoSciences dipstick (Abcam, Cambridge, UK), and spectrophotometric assays, respectively. Biochemical analyses were performed blindly at Bambino Gesù Hospital (Rome, Italy), which has long‐term expertise in this field …”