CMT 1 A: Motor Axonal Sprouting Neuromuscular Junction Loss in Animal Model

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J Neuropathol Exp Neurol. 2010 Feb 8

Motor Axonal Sprouting and Neuromuscular Junction Loss in an Animal Model of

Charcot-Marie-Tooth Disease.

Ang ET, Schäfer R, Baltensperger R, Wernig A, Celio M, Oliver SS.

From the Department of Medicine/Unit of Anatomy, Faculty of Science, University

of Fribourg, Fribourg, Switzerland (E-TA, MC, SSO); Department of Physiology II,

Faculty of Medicine, University of Bonn, Bonn, Germany (RS, AW); and Ecole

d'ingénieurs et d'architectes de Fribourg, Fribourg, Switzerland (RB).

ABSTRACT: 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.