Assessment of respiratory motor units in the mdx mouse model of Duchenne muscular dystrophy

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Murphy, Kevin H.
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University College Cork
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Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease characterised by the absence of the structural protein dystrophin. Respiratory failure is the leading cause of premature death in DMD. Although respiratory insufficiency is recognized as a hallmark of DMD, respiratory control is relatively understudied. We hypothesized that enhanced drive in respiratory motor pathways preserves ventilatory capacity compensating for severe respiratory muscle weakness. Male wild-type (n=23) and mdx (n=23) mice were studied. Breathing was examined during normoxia and chemo-challenge with hypercapnic-hypoxia. In urethane (1.7 g/kg i.p.) anaesthetised mice, diaphragm, external intercostal and genioglossus electromyogram (EMG) and motor unit recordings were performed during baseline conditions and in response to chemo-stimulation. Diaphragm muscle function was examined ex vivo. Diaphragm muscle function is severely impaired in young mdx mice. Despite substantial diaphragm muscle weakness, freely-behaving mdx mice can increase ventilation during chemostimulation with hypercapnic-hypoxia. Motor unit recordings revealed an increase in the number of active units for diaphragm and genioglossus muscle. There were no major differences in the firing frequency of motor units in the respiratory muscles. Diaphragm EMG activity was depressed in mdx mice during baseline and maximum chemostimulation, compared to wild-type. In conclusion, severe mechanical disadvantage of the diaphragm is evident across a range of stimulation frequencies, yet there is a preserved capacity to raise ventilation in young mdx mice indicating a significant ventilatory reserve. Motor unit remodelling is evident in the diaphragm of mdx mice, but ultimately diaphragm EMG activity is impaired. The combination of reduced neural activation of the diaphragm and intrinsic weakness reveals major compromise in the neuromuscular function of the diaphragm in mdx mice as early as 8 weeks of age. The novel observations of this study coupled with other work by our group suggest that support from accessory muscles is critical to the support of respiratory performance in mdx mice, which may have relevance to DMD.
mdx , Duchenne muscular dystrophy , Control of breathing , Motor units
Murphy, K. H. 2021. Assessment of respiratory motor units in the mdx mouse model of Duchenne muscular dystrophy. MRes Thesis, University College Cork.
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