Ricerc@Sapienza

Interleukin-6 (IL-6) is a pleiotropic cytokine able to exert pro-regenerative effects in muscle tissue and to induce catabolic/pro-inflammatory pathways, depending on the levels, the time of action and the activated signaling. Locally and transiently produced IL-6 positively influence muscle tissue, being required for satellite cell proliferation. Otherwise, persistent and sustained levels of circulating IL-6 have been reported to induce muscle atrophy and wasting.
Increased levels of serum IL-6 have been found under several physio-pathologic conditions, including aging, cancer cachexia and muscular dystrophies. Duchenne muscular dystrophy is a genetic disease characterized by a progressive degeneration of myofibers. Downstream the genetic defect, secondary mechanisms, as chronic inflammation and excessive ROS production, contribute to the progression of pathology. We demonstrated that elevated levels of circulating IL-6 exacerbates the dystrophic phenotype of mdx mice, more closely approximating human pathology. A key role of IL-6 in perturbing the redox-balance of dystrophic muscles has been also elucidated by our studies. Data from our group also highlighted an attenuated muscle pathology in mdx mice in which a short-term inhibition of IL-6 trans-signaling has been performed.
Basing on these evidences the main goal of the proposed project is to better clarify the impact of the stimulation/inhibition of IL-6 signaling on muscle homeostasis. To this aim I will use a mouse model in which IL-6 is overexpressed in a non-pathologic background, to evaluate the direct contribute of IL-6 in promoting mechanisms involved in the perturbation of skeletal muscle homeostasis, as the alteration of the redox-signaling cascade. Moreover, I will analyse a newly generated dystrophic model, knocked out for the expression of the IL-6 receptor alpha, to evaluate whether long-lasting interference with IL-6 signaling can ameliorate secondary symptoms of the disease.