Phd in MORPHOGENESIS AND TISSUE ENGINEERING

Thesis title: Understanding the contribution of IL-6 transignalling to DMD progression and implications for therapy

Duchenne Muscular Dystrophy (DMD) is a muscle wasting genetic disease caused by mutations in dystrophin gene. The absence of dystrophin protein triggers degenerative events, including necrosis, inflammation and fibrosis. A curative treatment for the disease is not currently available, despite the development of different therapeutical approaches aimed to restore dystrophin expression and this could be ascribed to the hostility of dystrophic microenvironment, that might interfere with the efficacy of therapeutic strategies. Mounting evidences support the role of IL-6 in fostering degenerative events in DMD muscle. In particular, IL-6 is a pleiotropic cytokine which exerts its functions in an hormetic manner: indeed, low or controlled levels of the cytokine are associated with pro-regenerative and anti-inflammatory actions, mainly mediated by the classical signalling, while deregulated levels correlate with pro-inflammatory and pro-oxidant responses, mostly ascribed to the activation of IL-6 transignalling. Based on this rational, the aim of the current study is to evaluate whether the interference with IL-6 transignalling is sufficient to mitigate dystrophic muscle degeneration, slowing down disease progression. The data collected suggested that the modulation of IL-6 transignalling during the necrotic phase of the disease stabilizes dystrophic muscle, attenuating muscle necrosis and preserving muscle functionality. Furthermore, the attenuation of later-stage muscle degeneration highlighted the protective action of our approach against the grave loss of functional muscle tissue over time, suggesting that IL-6 transignalling modulation could be a reliable strategy to slow down DMD progression, attenuating degenerative mechanisms dominating dystrophic muscle at both the acute and highly degenerative stages of the disease.