Dystrophin is required for organizing large acetylcholine receptor aggregates

Dystrophin is a cytoplasmic protein underlying the plasma membrane in normal skeletal muscle. Its absence leads to muscle degeneration as seen in Duchenne muscular dystrophy (DMD) and in mdx mice. One puzzling question in the study of dystrophinopathies is that in mdx muscles the neuromuscular junctions (NMJs) show little, if any, developmental defect, but morphological and functional abnormalities of NMJs are obvious after muscle damage and regeneration begin. This phenomenon leads us to hypothesize that dystrophin may be required for endplate maintenance and/or endplate remodeling in regenerating fibers. Here we show that the absence of dystrophin causes NMJ fragmentation in adult muscle fibers, and greatly reduces both spontaneous and agrin-induced acetylcholine receptor (AChR) clustering activities on cultured myotubes derived from satellite cells. The lower AChR clustering in mdx myotubes originates in the smaller size of each cluster and from a 72% reduction in the occurrence of large (> 10 micron 2) AChR clusters. Our results suggest dystrophin is involved in organizing small AChR clusters into large AChR aggregates during muscle regeneration, although it is not required for initiating the original AChR clustering activity.