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 mo...

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Bibliographic Details
Published in:Journal of neuropathology and experimental neurology 2010-03, Vol.69 (3), p.281-293
Main Authors: Ang, Eng-Tat, Schäfer, Ralf, Baltensperger, Richard, Wernig, Anton, Celio, Marco, Oliver, Sara Sancho
Format: Article
Language:English
Subjects:
Acetylcholine - metabolism
Animals
Biological and medical sciences
Charcot-Marie-Tooth Disease - genetics
Charcot-Marie-Tooth Disease - pathology
Charcot-Marie-Tooth Disease - physiopathology
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Disease Models, Animal
Disease Progression
Female
Growth Cones - physiology
Growth Cones - ultrastructure
Hindlimb - innervation
Hindlimb - physiopathology
Male
Medical sciences
Mice
Mice, Transgenic
Motor Neurons - cytology
Motor Neurons - physiology
Muscle Contraction - genetics
Muscle Weakness - genetics
Muscle Weakness - pathology
Muscle Weakness - physiopathology
Muscular Atrophy - genetics
Muscular Atrophy - pathology
Muscular Atrophy - physiopathology
Nerve Regeneration - genetics
Neurology
Neuromuscular Junction - pathology
Neuromuscular Junction - physiopathology
Neuronal Plasticity - genetics
Peripheral Nerves - pathology
Peripheral Nerves - physiopathology
Synaptic Transmission - genetics
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Summary: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.
ISSN:0022-3069
1554-6578
DOI:10.1097/NEN.0b013e3181d1e60f