Increased Circulating Levels of Interleukin‐6 Induce Perturbation in Redox‐Regulated Signaling Cascades in Muscle of Dystrophic Mice

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.

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

“…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].…”

“…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].…”

“…It has been demonstrated that the X-ROS signaling is altered in adult mdx hindlimb muscles but not in young dystrophic muscles, suggesting a relation between X-ROS alteration and DMD progression. However, in diaphragm muscle, which is the most severely affected muscle in mdx, an altered X-ROS signaling early before the onset of the necrotic phase of pathology (2 weeks of age) has been observed [79]. In particular, we recently reported that pre-necrotic mdx diaphragms showed an enhanced expression of both MT network components (α-, β-, and detyrosinated-tubulin) and gp91phox, the catalytic subunit of NOX2 complex, with an increased production of ROS compared to age-matched wild type mice [79].…”

“…However, in diaphragm muscle, which is the most severely affected muscle in mdx, an altered X-ROS signaling early before the onset of the necrotic phase of pathology (2 weeks of age) has been observed [79]. In particular, we recently reported that pre-necrotic mdx diaphragms showed an enhanced expression of both MT network components (α-, β-, and detyrosinated-tubulin) and gp91phox, the catalytic subunit of NOX2 complex, with an increased production of ROS compared to age-matched wild type mice [79]. The importance of the MT-network deregulation in dystrophin-deficient mice was also revealed in young mdx and wild type muscles in which the taxol-induced enhancement of MT density resulted in altered X-ROS signaling [78].…”

“…The aspecific mechanism of action of glucocorticoids could be a drawback of treatment, making unclear and controversial which molecular pathways provide the efficacy in DMD and which pathways are responsible for detrimental effects [111], hence the importance of identifying more specific drugs counteracting inflammation. Among these, the blockade of IL-6 activity in mdx mice, using a neutralizing antibody against the IL-6 receptor (moAb-IL6r), resulted in an enhanced robustness to dystrophic muscle, impeded the activation of a chronic inflammatory response, significantly reduced necrosis, prevented excessive ROS production, and activated the circuitry of muscle differentiation and maturation [28,79].…”