نبذة مختصرة : Several lines of evidence indicate that neuromuscular junction (NMJ) destruction and disassembly is an early phenomenon in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease. Here we analyzed by confocal and electron microscopy the NMJ structure in the diaphragm of Superoxide dismutase (SOD)1 G93A mice at symptom onset and we compared these observation with animals sacrificed at the pathological end stage. In young transgenic mice, which provide a model for familial ALS, the present findings showed marked denervation both in the diaphragm and in the gastrocnemius, which partially spares soleus muscle. At the clinical end stage even the soleus is slight denervated, but less severely than other muscles. In addition, the size of the synaptic vesicle (SV) pool was found reduced and alterations of mitochondria were observed in approximately 40% of the remaining presynaptic terminals. Treatment of SOD1 G93A mice with the anabolic steroid nandrolone during the presymptomatic stage preserved the diaphragm muscle mass and features indicative of synaptic activity, represented by the number of vesicles docked within 200 nm from the presynaptic membrane and area of acetylcholine receptor clusters. Furthermore, structural preservation of mitochondria was documented in presynaptic terminals, but innervation of diaphragm muscle fibers was only slightly increased in nandrolone-treated SOD1-mutant mice. Altogether the results point out and define fine structural alterations of diaphragm NMJs in the murine model of familial ALS at symptom onset, and indicate that nandrolone may prevent or delay structural alterations in NMJ mitochondria and stimulate presynaptic activity but does not prevent muscle denervation in the disease.
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