Translational consequences of novel neurodegenerative changes in dystrophic nerves of mdx rodent models for Duchenne Muscular Dystrophy (DMD)


Neuromuscular Junction in Disease

Poster Number: 115


Miranda Grounds, MD, Lakshana Thanigaiarasu, Vidya Krishnan


1. University of Western Australia, 2. University of Western Australia, 3. University of Western Australia

Background. In DMD and the dystrophic mdx mouse and dog models of DMD, repeated bouts of intrinsic skeletal muscle necrosis result in progressively altered neuromuscular junctions (NMJs): this is probably irreversible (Haddix et al., 2018. PMID: 3037989). We propose that these altered NMJs (indicating denervation) result in premature neurodegeneration in the associated dystrophic nerves.
This builds upon our extensive research into normal neuromuscular ageing, where time course studies show denervation of NMJs and myofibres, associated with neurodegeneration for motor and sensory nerves by 18 to 22 months(m) (Krishnan et al, 2016. PMID: 27030741; 2018. PMID: 30084046).
Objective. To test if there is premature progressive neurodegeneration in dystrophic nerves.
Approach. Peripheral nerves (sciatic and radial) were sampled from 3 rodent models of DMD: classic mdx and D2-mdx mice (aged 9 to 18m) and Dmdmdxrats (aged 8m), along with wild type (WT) strains (n= 7-10/group). Nerves were snap frozen, and proteins extracted and quantified using immunoblotting.
Results. Tau5 and S100β proteins were significantly increased in mdx (but not D2-mdx) sciatic nerves by 13m (~9m earlier than in normal ageing) and further increased by 18m; both proteins also increased in nerves of young Dmdmdxrats aged 8m (compared with WT), supporting pronounced disease severity in these dystrophic rats.
Conclusions. These novel observations of premature neurodegeneration in mdx mice and Dmdmdxrats indicate severe ongoing myonecrosis, and support the use of these 2 models for DMD research. This neurodegeneration presents new targets for drug therapy, and provides a valuable new pre-clinical biomarker to monitor long-term benefits of therapies designed to reduce myonecrosis. In older DMD boys such progressive neurodegeneration over many years is likely to contribute to loss of muscle function, and complicate the evaluation of efficacy of clinical therapies that aim to maintain muscle function.