A highlight on the effect of DMD in peripheral innervation: alterations of the Schwann cells-axons crosstalk in the sciatic nerve of dystrophic mdx mice

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease, characterized by the lack of the cytoskeletal protein dystrophin (Dp427) in skeletal muscles; shorter isoforms also are expressed in different cells types, as Dp116 in Schwann cells in the peripheral nervous system. By binding a multiple protein complex, Dp116 plays a fundamental role in the myelin integrity and in fiber conduction properties. Our previous studies on the sciatic nerves of wild-type and mdx mice, a model of DMD lacking the sole Dp427, highlighted a significant reduction on myelin basic protein levels indicating an alteration of myelin integrity, as well as in Abeta- mechanoreceptor fiber excitability. Considering the importance of the role of Dp116-DGC in myelin, we analyzed three major complex components: alpha- and beta-DGs, and dystrobrevin. Levels, distribution and intensity of immunolabeling of all three proteins were significantly reduced in mdx mouse sciatic nerves compared to wild-type, with consequences on myelin organization. Since the expression of Dp116 was not equally altered, we theorized as a possible cause activation of proinflammatory extracellular matrix metalloproteinases (MMP). Furthermore, Western immunoblot demonstrated activation of the pro-inflammatory MMP-2 and MMP-9 as an upstream determinant for Dp116-DGC degradation and consequent deregulation of SC-axon signaling. This was also confirmed by parallel studies showing a quantative reduction in cholinergic receptors…… Altogether, these results on the mdx mouse highlight a significant impact of DMD on peripheral nerves, which may lead to the development of peripheral neuropathies and compromised muscular control.