Dp427, is characterized by progressive skeletal muscle degeneration, although increasing evidence indicates a broader neuromuscular dysfunction. Here, we identify impaired Schwann cell (SC) homeostasis in the sciatic nerve of dystrophic mdx mice. Integrated molecular, immunofluorescence, ultrastructural, and electrophysiological analyses demonstrate that sciatic nerves from 6 to 7-week-old mdx mice exhibit downregulation of key myelin proteins (MBP, P0, PMP22), compared with age-matched wild type mice. Despite preserved SC dystrophin isoforms (Dp116 and Dp71), core components of the dystrophin-associated glycoprotein complex (DGC), namely α- and β-dystroglycan and dystrobrevin, are significantly reduced. Concomitant activation of matrix metalloproteinases (MMP)-2 and MMP-9 is consistent with enhanced proteolytic processing and DGC destabilization. These alterations are accompanied by reduced mRNA and protein expression of GABA-A and GABA-B receptors and the GABA-synthesizing enzymes GAD65 and GAD67, indicating perturbed autocrine/paracrine GABAergic signaling at the SC-axon interface, further supported by altered neuregulin-1/ErbB2 signaling. Furthermore, sensory Aβ-fibers from mdx mice exhibit mild hypoexcitability, altered refractoriness, and impaired tolerance to high-frequency stimulation, consistent with impaired myelin integrity and diminished electrical insulation, confirmed by ultrastructural evidence of focal myelin abnormalities affecting a subset of nerve fibers. Notably, none of the parameters examined in 10-day-old mdx mice showed detectable alterations, suggesting that sciatic nerve abnormalities become evident after the onset of overt muscle degeneration. Altogether, these findings identify the sciatic nerve as a previously underappreciated site of disease-associated alterations in DMD and a potential target for future therapeutic investigations.
Dysregulation of the Schwann cell GABAergic system and Aβ-fibers conduction abnormalities in the sciatic nerve of the mdx mouse model of Duchenne muscular dystrophy / Di Nuzzo, S., Mastrostefano, F., Soligo, M., Mohamed, T., Bonalume, V., De Santis, E., Grassi, F., Ferretti, V., Tata, A.M., Magnaghi, V., De Stefano, M.E.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 228:(2026). [10.1016/j.nbd.2026.107534]
Dysregulation of the Schwann cell GABAergic system and Aβ-fibers conduction abnormalities in the sciatic nerve of the mdx mouse model of Duchenne muscular dystrophy
Silvia Di NuzzoCo-primo
Data Curation
;Francesca MastrostefanoCo-primo
Data Curation
;Marzia SoligoData Curation
;Eleonora De SantisData Curation
;Francesca GrassiWriting – Review & Editing
;Valentina FerrettiWriting – Review & Editing
;Ada Maria TataWriting – Review & Editing
;Valerio MagnaghiData Curation
;Maria Egle De Stefano
Ultimo
Conceptualization
2026
Abstract
Dp427, is characterized by progressive skeletal muscle degeneration, although increasing evidence indicates a broader neuromuscular dysfunction. Here, we identify impaired Schwann cell (SC) homeostasis in the sciatic nerve of dystrophic mdx mice. Integrated molecular, immunofluorescence, ultrastructural, and electrophysiological analyses demonstrate that sciatic nerves from 6 to 7-week-old mdx mice exhibit downregulation of key myelin proteins (MBP, P0, PMP22), compared with age-matched wild type mice. Despite preserved SC dystrophin isoforms (Dp116 and Dp71), core components of the dystrophin-associated glycoprotein complex (DGC), namely α- and β-dystroglycan and dystrobrevin, are significantly reduced. Concomitant activation of matrix metalloproteinases (MMP)-2 and MMP-9 is consistent with enhanced proteolytic processing and DGC destabilization. These alterations are accompanied by reduced mRNA and protein expression of GABA-A and GABA-B receptors and the GABA-synthesizing enzymes GAD65 and GAD67, indicating perturbed autocrine/paracrine GABAergic signaling at the SC-axon interface, further supported by altered neuregulin-1/ErbB2 signaling. Furthermore, sensory Aβ-fibers from mdx mice exhibit mild hypoexcitability, altered refractoriness, and impaired tolerance to high-frequency stimulation, consistent with impaired myelin integrity and diminished electrical insulation, confirmed by ultrastructural evidence of focal myelin abnormalities affecting a subset of nerve fibers. Notably, none of the parameters examined in 10-day-old mdx mice showed detectable alterations, suggesting that sciatic nerve abnormalities become evident after the onset of overt muscle degeneration. Altogether, these findings identify the sciatic nerve as a previously underappreciated site of disease-associated alterations in DMD and a potential target for future therapeutic investigations.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
