Abstract
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein. Skeletal muscle weakness and eventual muscle degradation due to loss of dystrophin are well-documented pathological hallmarks of DMD. In contrast, the neuropathology of this disease remains understudied despite the emerging evidence of neurological abnormalities induced by dystrophin loss. Using quantitative morphological analysis of nerve sections, we characterize axonopathies in the phrenic and hypoglossal (XII) nerves of mdx mice. We observe dysfunction in these nerves – which innervate the diaphragm and genioglossus respectively – that we propose contributes to respiratory failure, the most common cause of death in DMD. These observations highlight the importance in the further characterization of the neuropathology of DMD. Additionally, these observations underscore the necessity in correcting both the nervous system pathology in addition to skeletal muscle deficits to ameliorate this disease.
Highlights
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein
While the function of dystrophin and pathophysiology of DMD in skeletal muscle is well-described in this model, recent evidence suggests that dystrophin may play an important role in the nervous system[5]
We demonstrate that mdx mice exhibit a motor neuron axonopathy in the phrenic and hypoglossal (XII) nerves, which implies that an underlying neuropathology may contribute to the characteristic respiratory failure of DMD
Summary
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein. We observe dysfunction in these nerves – which innervate the diaphragm and genioglossus respectively – that we propose contributes to respiratory failure, the most common cause of death in DMD. These observations highlight the importance in the further characterization of the neuropathology of DMD. We demonstrate that mdx mice exhibit a motor neuron axonopathy in the phrenic and hypoglossal (XII) nerves, which implies that an underlying neuropathology may contribute to the characteristic respiratory failure of DMD. We provide some of the first direct evidence that nervous system dysfunction may represent an important, but often overlooked, source of respiratory insufficiency in DMD
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