PRE-CLINICAL ASSESSMENT OF THE ROLE OF THE COMPLEMENT SYSTEM IN TRIGGERING FIBROSIS IN DUCHENNE MUSCULAR DYSTROPHY: TOWARDS NOVEL THERAPEUTIC TARGETS

In Duchenne muscular dystrophy (DMD), the absence of functional dystrophin in muscle fibers causes repetitive cycles of degeneration/ regeneration, paralleled by a condition of chronic inflammation and, lately, leading to progressive fibrosis and loss of function. Recent data in BL10-mdx mouse, the most widely used model of DMD, support the hypothesis that an over-expression of the complement component 1 (C1), in inflamed muscle, could reinforce fibrosis via WNT- β-catenin-TGF-β2 axis (Florio et al., 2023). These promising results pave the way for a deeper investigation, also considering the availability of drugs effectively targeting the complement cascade in many rare diseases. We evaluated, via real time PCR, the expression of C1q and C3 complement components in gastrocnemius (GC) muscle of BL-10 mdx and D2-mdx mice, with respect to WT ones, at 4, 12 and 28 weeks of age. We found a strict correlation between C1q and C3 overexpression and the peak of unhealthy tissue in GC muscle of BL-10 mdx and D2-mdx in the early stage of pathology. On the other hand, our results on Tgfβ2 and β-catenin gene expression were not in favour of a clear involvement of this pathway in fibrotic program. In fact, this process seems to be regulated mostly via TGFβ1 that was overexpressed in both models. In addition, a marker of fibro-adipogenic precursors (PDGFra) was upregulated at 28 weeks in D2 -mdx mice, in line with the more severe fibrotic phenotype. Further insights are ongoing to better investigate the role of the complement system in DMD pathogenesis