Therapeutic trials and translational gaps: respiratory outcomes in the mdx mouse model of Duchenne muscular dystrophy
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Date
2025
Authors
Maxwell, Michael N.
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University College Cork
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Abstract
Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder marked by progressive muscle degeneration and respiratory failure, primarily due to mutations in the DMD gene encoding dystrophin. The mdx mouse, which lacks functional dystrophin, is the most widely used preclinical model for DMD, but the trajectory of respiratory dysfunction and the effects of various interventions on respiratory musculature in this model remain incompletely defined. This thesis comprehensively investigates the impact of acute intermittent hypoxia (AIH), chronic N-acetylcysteine (NAC) administration, intermittent prednisone, and combined prednisone plus NAC treatment on respiratory system performance in the mdx mouse, while also evaluating the translational value of this model for studying respiratory decline in DMD.
The initial focus was on AIH, a therapeutic intervention that exposes subjects to repeated short bouts of hypoxia, which in other neuromuscular disorders has been shown to induce respiratory plasticity and enhanced ventilatory capacity. However, in mdx mice, AIH failed to elicit ventilatory long-term facilitation (LTF). While there was a significant increase in minute ventilation post-AIH, this was matched by a corresponding rise in metabolic CO₂ production, resulting in no net improvement in ventilatory efficiency. This suggests that AIH does not induce beneficial neural or muscular adaptations in the dystrophic respiratory system of mdx mice, limiting its therapeutic potential for DMD.
Chronic administration of NAC, a thiol-based antioxidant with anti-inflammatory and anti-fibrotic properties, was evaluated over a three-month period. Despite its mechanistic promise, chronic NAC treatment did not improve diaphragm force generation, reduce fibrosis, or diminish immune cell infiltration in the mdx diaphragm. Respiratory parameters, including ventilatory responsiveness to hypercapnic hypoxia and peak inspiratory pressures, remained unaffected. These findings indicate that NAC monotherapy is insufficient to counteract the multifactorial dystropathology of DMD, at least in the context of the mdx mouse model.
Intermittent prednisone, the mainstay corticosteroid therapy in DMD, and its combination with NAC were also assessed. Neither regimen resulted in significant improvements in diaphragm specific force, respiratory muscle electromyogram (EMG) amplitudes, or overall respiratory system performance. The lack of additive or synergistic benefit from combining anti-inflammatory and antioxidant strategies further underscores the complexity of mdx pathology and the limitations of targeting isolated pathways.
A critical component of this thesis was the longitudinal characterization of respiratory function in mdx mice. Despite severe and progressive diaphragm pathology, including extensive fibrosis by 16 months of age, mdx mice maintained stable peak inspiratory pressures and ventilatory capacity until advanced age. This contrasts starkly with the human DMD phenotype, where respiratory decline is evident from early adolescence and progresses steadily. The data suggest that compensatory recruitment of accessory respiratory muscles in mdx mice masks respiratory insufficiency until late in the disease course, thereby reducing the translational relevance of this model for studying early-stage respiratory decline and therapeutic intervention.
In summary, this thesis demonstrates that AIH, chronic NAC, intermittent prednisone, and their combination do not meaningfully preserve respiratory function in the mdx mouse model of DMD. The findings highlight the need for multitarget therapeutic strategies that concurrently address oxidative stress, inflammation, and fibrosis. Furthermore, the resilience of the mdx respiratory system limits its utility for preclinical studies aimed at early intervention to ameliorate ventilatory insufficiency, emphasizing the need for next-generation animal models that more faithfully recapitulate the human disease trajectory. The work also calls for the refinement of clinical biomarkers—to move beyond forced vital capacity (FVC) and maximal inspiratory pressure (MIP)—to enable earlier detection of respiratory compromise and more sensitive assessment of therapeutic efficacy. Collectively, this thesis provides a critical framework for reevaluating both therapeutic development and model selection in DMD research, advocating for approaches that prioritize human-relevant pathophysiological endpoints and combinatorial treatment strategies.
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Keywords
Inspiratory pressure , Duchenne muscular dystrophy , Respiratory EMG , Antioxidant , mdx , Acute intermittent hypoxia , Long term facilitation , Neuromechanical efficiency , Neural respiratory drive , Tension-time index , Respiratory electromyogram spectrum parameters
Citation
Maxwell, M. N. 2025. Therapeutic trials and translational gaps: respiratory outcomes in the mdx mouse model of Duchenne muscular dystrophy. PhD Thesis, University College Cork.