Motor axonopathies in a mouse model of Duchenne muscular dystrophy

Abstract

Materials and Methods experimental animals. All mice were approved by the Duke University Institutional Animal Care and Use Committee (IACUC) under protocol A233-171-10. All experiments were performed in accordance with relevant guidelines and regulations. All protocols involving mice were approved by Duke University IACUC. C57Bl6/J, wildtype, and C57Bl/10ScSn-Dmd mdx /J (mdx), mice were obtained from the Jackson Laboratory and housed at the Duke University Division Laboratory Animal Resources.

Breathing in Duchenne muscular dystrophy: translation to therapy

“…Dystrophin deficiency also causes motor neuron axonopathy of the respiratory nerves. Motor neuron axonopathy is present in both the phrenic and hypoglossal (XII) nerves, which implies that an underlying neuropathology also contributes to the characteristic respiratory failure of DMD (Dhindsa et al., 2020). Further, there is significant demyelination and loss of large‐calibre axons in these mice.…”

“…Further, there is significant demyelination and loss of large‐calibre axons in these mice. Finally, mitochondrial abnormalities were evident in the phrenic and hypoglossal nerves (Dhindsa et al., 2020).…”

“…It is also worth noting that in many studies, decreased basal ventilation in dystrophic animals is linked to decreased respiratory frequency (including during hypercapnia), which might suggest disruption to intrinsic neural network function and rhythmogenesis (or peripheral sensory inputs to the network). It is evident that flow‐ and volume‐related parameters are ultimately impaired in the course of dystrophic disease progression, which could relate to impaired neural drive to breathe due to altered neuromodulation or confirmed axonopathy in respiratory motor pathways (Dhindsa et al., 2020), compounding progressive neuromuscular impairment and explicit muscle pathology.…”

Dystrophic Dmd rats show early neuronal changes (increased S100β and Tau5) at 8 months, supporting severe dystropathology in this rodent model of Duchenne muscular dystrophy

“…While we measured protein levels in dystrophic nerves that innervate limb skeletal muscles, a recent study using electron microscopy describes striking pathological changes in phrenic and hypoglossal (XII) nerves of mdx mice (n=3) aged 12 months (Dhindsa et al, 2020), with severe axonal demyelination and mitochondrial abnormalities that were pronounced for large calibre axons, and it was concluded that this degeneration was initiated at the NMJ.…”

Breathing new life into therapies for Duchenne muscular dystrophy

“…Respiratory failure is the leading cause of premature death in severe muscular dystrophy. Studies in the mdx mouse and related models have revealed that respiratory compromise arises owing to dysfunction at multiple levels of the respiratory control network (Burns et al., 2017; Dhindsa et al., 2020). Sleep‐disordered breathing is common in DMD, and exposure to resultant chronic intermittent hypoxia is likely to exacerbate deficiencies in respiratory system performance.…”