Analysis of neuromuscular junctions and effects of anabolic steroid administration in the SOD1G93A mouse model of ALS.
Several lines of evidence indicate that neuromuscular junction (NMJ) destruction and disassembly is an early phenomenon in amyotrophic lateral sclerosis (ALS). Here we analyzed by confocal and electron microscopy the NMJ structure in the diaphragm of SOD1G93A mice at symptom onset. In these mice, which provide a model for familial ALS, diaphragm denervation (~50%) as well as gastrocnemius denervation (~40%) was found. In addition, the size of the synaptic vesicle pool was reduced and alterations of mitochondria were observed in approximately 40% of the remaining presynaptic terminals. Chronic treatment of SOD1G93A mice with the anabolic steroid nandrolone during the presymptomatic stage preserved the diaphragm muscle mass and features indicative of synaptic activity. These features were represented by the number of vesicles docked within 200 nm from the presynaptic membrane and area of acetylcholine receptor clusters. Structural preservation of mitochondria was documented in presynaptic terminals. However, 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 during the disease.
Dept. of Medical Biotechnology and Translational Medicine, University of Milan, Italy.
Valentina
V
Cappello
Elena
E
Vezzoli
Marco
M
Righi
Matteo
M
Fossati
Raffaella
R
Mariotti
Arianna
A
Crespi
Marco
M
Patruno
Marina
M
Bentivoglio
Grazia
G
Pietrini
Maura
M
Francolini
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009154:Mutation; D009277:Nandrolone / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics / Q000503:physiopathology / Q000648:ultrastructure*; D017729:Presynaptic Terminals / Q000502:physiology / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013572:Synaptic Vesicles / Q000648:ultrastructure
D045930:Anabolic Agents; C000606290:SOD1 protein, human; D009277:Nandrolone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1