Duchenne muscular dystrophy (DMD) is an X-linked
myopathy caused by
dystrophin deficiency.
Dystrophin is present intracellularly at the sarcolemma, connecting actin to the
dystrophin-associated
glycoprotein complex. Interestingly, it is enriched postsynaptically at the neuromuscular junction (NMJ), but its synaptic function is largely unknown.
Utrophin, a
dystrophin homologue, is also concentrated at the NMJ, and upregulated in DMD. It is possible that the absence of
dystrophin at NMJs in DMD causes neuromuscular transmission defects that aggravate
muscle weakness. We studied NMJ function in mdx mice (lacking
dystrophin) and wild type mice. In addition, mdx/utrn(+/-) and mdx/utrn(-/-) mice (lacking
utrophin) were used to investigate influences of
utrophin levels. The three Duchenne mouse models showed
muscle weakness when comparatively tested in vivo, with mdx/utrn(-/-) mice being weakest. Ex vivo muscle contraction and electrophysiological studies showed a reduced safety factor of neuromuscular transmission in all models. NMJs had ~ 40% smaller miniature endplate potential amplitudes compared with wild type, indicating postsynaptic sensitivity loss for the
neurotransmitter acetylcholine. However, nerve stimulation-evoked endplate potential amplitudes were unchanged. Consequently, quantal content (i.e. the number of
acetylcholine quanta released per nerve impulse) was considerably increased. Such a homeostatic compensatory increase in
neurotransmitter release is also found at NMJs in
myasthenia gravis, where
autoantibodies reduce
acetylcholine receptors. However, high-rate nerve stimulation induced exaggerated endplate potential rundown. Study of NMJ morphology showed that fragmentation of
acetylcholine receptor clusters occurred in all models, being most severe in mdx/utrn(-/-) mice. Overall, we showed mild 'myasthenia-like' neuromuscular synaptic dysfunction in several Duchenne mouse models, which possibly affects
muscle weakness and degeneration.