Duchenne Muscular Dystrophy affects peripheral innervation: observations on the sensory motor sciatic nerve

Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by lack of the cytoskeletal protein dystrophin (Dp427). Short dystrophin isoforms also exist, such as the Dp116 expressed in Schwann cells (SCs). Dp116 binds to the dystrophin-associated glycoprotein complex (DGC), which is crucial for maintaining myelin integrity. Our previous data on the sciatic nerve (SN) of mdx mice, an animal model for DMD, revealed significantly lower expression of myelin proteins and GABA receptors, as well as reduced excitability of sensory Aβ-mechanoreceptor fibers, compared to wild-type (wt) mice. In this study, we analyzed the levels and localization of Dp116 and three core DGC proteins: α-dystroglycan (DG), β-DG, and β-dystrobrevin. In the SN of mdx mice, all proteins exhibited significant reductions compared to wt mice, except for Dp116, suggesting that disruption of the complex is a primary alteration. Levels of active matrix metalloproteinases 2 and 9, which target α- and β-DG and may originate from inflamed muscles, were elevated, potentially affecting the stability of the DGC in SCs. Finally, given that cholinergic signaling is a renowned regulator of axon-SC crosstalk, we analyzed expression of M2 metabotropic (promyelinating) and α7 ionotropic (anti-inflammatory) acetylcholine receptors, finding significant reductions of both in mdx mice compared to wt. Collectively, our data indicate that DMD may have substantial effects on peripheral sensory-motor muscle control