Motor axonal sprouting and neuromuscular junction loss in an animal model of Charcot-Marie-Tooth disease.
Muscle weakness in Charcot-Marie-Tooth Type 1A disease (CMT1A) caused by mutations in peripheral myelin protein 22 (PMP22) has been attributed to an axonopathy that results in denervation and muscle atrophy. The underlying pathophysiological mechanisms involved are not understood. We investigated motor performance, neuromuscular junctions (NMJs), physiological parameters, and muscle morphometry of PMP22 transgenic mice. Neuromuscular junctions were progressively lost in hindlimb muscles of PMP22 transgenic mice, but their motor performance did not completely deteriorate during the observation period. There was considerable variability, including in laterality, in deficits among the animals. Cross-sectional areas and mean fiber size measurements indicated variable myofiber atrophy in hindlimb muscles. There was substantial concomitant axonal sprouting, and loss of neuromuscular junctions was inversely correlated with the accumulated length of axonal branches. Synaptic transmission studied in isolated nerve/muscle preparations indicated variable partial muscle denervation. Acetylcholine sensitivity was higher in the mutant muscles, and maximum tetanic force evoked by direct or indirect stimulation, specific force, and wet weights were markedly reduced in some mutant muscles. In summary, there is partial muscle denervation, and axons may retain some regenerative capacity but fail to reinnervate muscles in PMP22 transgenic mice.
Ang
Eng-Tat
ET
Department of Medicine/Unit of Anatomy, Faculty of Science, University of Fribourg, Fribourg, Switzerland.
Schäfer
Ralf
R
Baltensperger
Richard
R
Wernig
Anton
A
Celio
Marco
M
Oliver
Sara Sancho
SS
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020439:Growth Cones / Q000502:physiology* / Q000648:ultrastructure; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology*; D009119:Muscle Contraction / Q000235:genetics; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009416:Nerve Regeneration / Q000235:genetics; D009469:Neuromuscular Junction / Q000473:pathology* / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000235:genetics; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000235:genetics
D000109:Acetylcholine