Duchenne muscular dystrophy (DMD) is a severe x-linked myodegenerative disease caused by defective expression of the full-length dystrophin (Dp427), a large cortical cytoskeletal protein. A few studies from our laboratory described significant retrograde effects of muscle degeneration on peripheral autonomic innervation, as well as a direct impact of the lack of dystrophin on axonal dynamics in vivo and in vitro (!-3). However, little or none has been reported on the specific outcome that this disease has on motor neurons (MNs) innervating limb muscles (among the most severely affected) and on the crosstalk that their axons establish with Schwann cells (SCs), neither in DMD patients nor in animal models (e.g. mdx mice). This aspect is of particular importance as the impact that lack of Dp427 and other dystrophins on the nervous system begins during embryonic development, in some respect framing DMD among neurodevelopmental diseases.
The main goal of this project is to begin a first analysis of the biomolecular mechanisms and intracellular pathways that are potentially altered in MNs and peripheral nerves in severe muscular pathologies, as the DMD. Particular attention will be paid to the repercussions that neuromuscular alterations have on intraspinal MN connectivity, axon growth, myelination, and regenerative capacities. The study will be conducted on the mdx mouse, a well-known experimental model of DMD, and their wild type.
As great effort is spent in finding pharmacological strategies aimed at muscular regeneration in DMD. However, damages to nervous system as, in particular, to autonomic innervation and involuntary organ regulation, sensory inputs to CNS and, not ultimately, MNs and NMJ are largely overlooked, especially in terms of therapeutic aspects.
The main purpose of this study dystrophy-related alterations in MN connectivity to damaged skeletal muscles, in both adult mdx mice (characterized by heavy cycles of muscle degeneration/regeneration) and young postnatal mice (P5, P10), when eyes are still closed, hind limb use not yet at its full and important muscle degeneration has not yet begun.
With this study we expected to shed a first light on the:
1. morpho-functional alterations in MN connectivity and axon myelination dynamic, yet unexplored;
2. differences in some epigenetic factors ruling MN development, differentiation and degeneration, as levels of specific miR already described in other neuromuscular pathologies;
3. novel therapies implementing those adopted in the treatment of DMD, which could be effective not only for muscle regeneration, but also to restore and/or maintain appropriate neuromuscular connections and nerve conductance.
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