Implications of increased S100ß and Tau5 proteins in dystrophic nerves of two mdx mouse models for Duchenne muscular dystrophy.

ABSTRACT

This study investigates changes with respect to increasing protein levels in dystrophic nerves of two mdx mouse models of Duchenne muscular dystrophy (DMD). We propose that these nerve changes result from progressive ongoing damage to neuromuscular junctions (NMJs) due to repeated intrinsic bouts of necrosis in dystrophic muscles. We compared sciatic nerves from classic mdx mice aged 13, 15 and 18 months (M), with D2.mdx mice (on DBA2 background) aged 9 and 13 M, using immunoblotting to quantify levels of 7 proteins. The neuronal proteins S100ß and Tau5 were increased by 13 M in mdx nerves (compared with WT), indicating ongoing myonecrosis in this strain. In striking contrast there was no difference in levels of these neuronal proteins for D2.mdx and D2.WT sciatic nerves at 13 M, indicating reduced myonecrosis over this time in D2.mdx mice compared with mdx. These novel changes in mdx sciatic nerves by 13 M, suggest early denervation or neurodegeneration of dystrophic nerves that is likely irreversible and progressive. This neuronal readout of persistent myonecrosis may provide a useful new long-term biomarker for preclinical studies that aim to reduce myonecrosis, plus such neuronal changes present potential new drug targets to help maintain the function of DMD muscles.