Sensorimotor peripheral innervation in Duchenne Muscular Dystrophy: a spotlight on the sciatic nerve of dystrophic mdx mice

Duchenne muscular dystrophy (DMD) is characterized by the lack of dystrophin (Dp427). Along or in substitution of Dp427, different tissues other than skeletal muscles also express shorter dystrophin isoforms, such as the Dp116, characteristic of myelinating Schwann cells (SCs). By binding to a large multiprotein complex (DGC), organized around the α- and β-dystroglycan (DG) dimer, Dp116 contributes to myelin integrity and nerve fiber conduction. Along this, also several mediators, including GABA, are involved in SC-axon crosstalk, crucial for the structural and functional integrity of nerve fibers. To uncover the impact of DMD on peripheral sensorimotor fibers, we analyzed in the sciatic nerve of dystrophic mdx mice, the expression and localization of several myelin proteins, Dp116-DGC components, GABAA (α4, β3, δ) and GABAB-1b receptor subunits. Compared to the wild-type, the level, localization, and intensity of immunolabeling of all proteins analyzed in mdx mice were significantly altered, indicating disruption of both myelin integrity and SC-axon crosstalk. This was confirmed by electrophysiological recordings showing a significant reduction in Abeta-mechanoreceptor fiber excitability. Finally, increased levels of gelatinases 2 and 9, both targeting α and β-DG, suggest that cleavage of the Dp116-DGC within the myelin sheet, induced by retrograde inflammatory signals from muscle, could be a primary upstream signal causing progressive deterioration of sensorimotor nerves