Neuropathology of the medulla in the mdx/utrophin-deficient Duchenne Muscular Dystrophy mouse model

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by the absence of dystrophin, resulting in respiratory failure. Utrophin is endogenously upregulated as a compensatory mechanism in the DMD mouse mode – the mdx mouse – thereby allowing the mice to compensate for the lack of dystrophin. The mdx;utrn-/- mouse, lacking both dystrophin and utrophin, exhibits severe respiratory deficits, including early-onset diaphragm fibrosis and inflammation, impaired ventilation, and premature death by ~13 weeks, closely mirroring pediatric DMD respiratory pathology. Approximately 1/3 of DMD patients exhibit neurological impairments because of dystrophin deficiency, but the impact of this on central respiratory control centers is unclear. The medulla houses the rhythm-generating neurons and neural circuits essential for breathing, and we sought to examine the impact of dystrophin deficiency on the medulla. Thus, the aim of this study is to identify the cellular and molecular alterations in the medulla that might contribute to central respiratory dysfunction in the mdx;utrn-/- mouse model of DMD. We performed post-mortem immunohistochemistry (IHC) and proteomic profiling of mdx;utrn-/- at its terminal stage and age-matched wild-type medulla (n=3). IHC revealed significant loss of ChAT + neurons and increased microglial activation in the hypoglossal motor neuron pool of mdx;utrn-/- mice, responsible for innervation of the genioglossus muscle which is important for upper airway patency. Proteomic analysis identified 182 upregulated and 266 downregulated proteins in mdx;utrn-/- medulla, with dysregulation of Wnt/cadherin signaling that which suggests compromised neuronal development, axon guidance, synapse formation, and neurogenesis. Further, proteins involved in myelination and oligodendrocyte functions were significantly reduced. These findings demonstrate that central neuropathology exists in the medulla and might contribute to respiratory insufficiency in mdx;utrn-/- mice which can also impact control of breathing in patients with DMD Funding: NHLBI R01HL171282 (MKE) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.