Respiratory neuroplasticity in a pre-clinical model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disorder caused by dystrophin deficiency, resulting in progressive skeletal muscle degeneration. Respiratory muscles are critically affected, and ventilatory insufficiency remains the leading cause of death in individuals with DMD. Although current respiratory therapies and corticosteroid regimens attenuate symptoms, they do not reverse underlying pathophysiology, underscoring the need for therapies that preserve and enhance ventilation long-term. Acute intermittent hypoxia (AIH) has emerged as a promising neuromodulatory approach capable of strengthening respiratory function by inducing long-term facilitation (LTF) of respiratory motor output. AIH-induced LTF has demonstrated clinical benefit in individuals with spinal cord injury and amyotrophic lateral sclerosis, yet its therapeutic potential in DMD has not been explored. Importantly, AIH-induced LTF is serotonin-dependent, mediated in part through 5-HT2A receptor signaling. Our proteomics data reveal a 3.8-fold reduction in 5-HT2A receptor expression in mdx mice compared with wild-type controls, suggesting a potential impairment in serotonin-mediated plasticity. Given this receptor downregulation, alongside chronic inflammation associated with DMD, we hypothesized that respiratory neuroplasticity would be diminished in mdx mice. We exposed C57BL/10ScSn-Dmdmdx/J (mdx) and C57Bl/10ScSnJ controls mice (3-4 months old) to 3, 1-minute episodes of hypoxia (10% O 2 ), interspersed by 3-minute normoxic intervals (60% O 2 ). Integrated hypoglossal nerve burst activity was measured at baseline, during hypoxic episodes and up to 60 minutes post-AIH. Preliminary findings suggest that hypoglossal LTF, assessed as a percent change in burst amplitude from baseline to 60 mins post-AIH, is attenuated in mdx versus wild type mice (65 ± 42% vs. 90 ± 32%). Ongoing studies will assess whether short-term prednisolone pretreatment mitigates neuroinflammation and restores LTF in mdx mice. 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.