Dystrophic Dmdmdx rats show early neuronal changes (increased S100ß and Tau5) at 8 months, supporting severe dystropathology in this rodent model of Duchenne muscular dystrophy.

ABSTRACT

The intrinsic necrosis of skeletal muscles in animal models of Duchenne muscular dystrophy (DMD) damages neuromuscular junctions (NMJs) with progressively altered NMJs associated with denervation and premature changes in dystrophic nerves. In the mdx mouse model of DMD, the proteins S100ß and Tau5 are significantly increased in sciatic nerves by 13 months (M) of age, far earlier (by 9 M) than in normal wildtype (WT) nerves. Since dystrophic Dmdmdx rats are reported to have a more severe dystropathology than mdx mice, we hypothesised that Dmdmdx rat nerves would show earlier neuronal changes compared with mdx nerves. We quantified levels of 8 proteins (by immunoblotting) in sciatic and radial nerves from young adult Dmdmdx rats (aged 8 M) and mdx mice (9 M), plus levels of 7 mRNAs (by qPCR) in rat nerves only. Sciatic nerves of 8 M Dmdmdx rats had more consistently increased levels of S100ß and Tau5 proteins, compared with 9 M mdx mice, supporting pronounced dystropathology in the rat model. There were no differences for mRNA levels, apart from higher gelsolin mRNA in Dmdmdx sciatic nerves. The pronounced protein changes in Dmdmdx nerves indicate a severe ongoing myonecrosis, and likely consequent myofibre denervation, for the dystrophic rat model. These data support increased neuronal proteins in dystrophic nerves as a novel pre-clinical readout of ongoing myonecrosis for DMD research. In older DMD boys, such progressive neuronal changes over many years are likely to contribute to loss of muscle function, and may complicate evaluation of late-onset clinical therapies.