Abstract
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration aggravated by sterile inflammation and is also associated with cognitive impairment and low bone density. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. Duchenne muscular dystrophy (DMD) alters P2RX7 signaling in both muscle and inflammatory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMDmdx mouse model. As P2RX7 is an attractive target in a range of human diseases, specific antagonists have been developed. Yet, these will require lengthy safety testing in the pediatric population of Duchenne muscular dystrophy (DMD) patients. In contrast, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can act as P2RX7 antagonists and are drugs with an established safety record, including in children. We demonstrate here that AZT (Zidovudine) inhibits P2RX7 functions acting via the same allosteric site as other antagonists. Moreover, short-term AZT treatment at the peak of disease in DMDmdx mice attenuated the phenotype without any detectable side effects. Recovery was evident in the key parameters such as reduced sarcolemma permeability confirmed by lower serum creatine kinase levels and IgG influx into myofibres, decreased inflammatory cell numbers and inflammation markers in leg and heart muscles of treated mice. Moreover, this short-term therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Given these results, we postulate that AZT could be quickly re-purposed for the treatment of this highly debilitating and lethal disease. This approach is not constrained by causative DMD mutations and may be effective in alleviating both muscle and non-muscle abnormalities.
Highlights
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder with X-linked inheritance
We have previously demonstrated the therapeutic impact of both genetic ablation and pharmacological blockade of P2RX7 in mdx mice in vivo
A p-value of < 0.05 was considered statistically significant, and the values are reported as follows in figures: *p < 0.05, **p < 0.01, ***p < 0.001. It has not been known whether Nucleoside Reverse Transcriptase Inhibitors (NRTIs) bind directly to P2RX7 and, if so, where or whether they have an indirect effect
Summary
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder with X-linked inheritance. Affected boys suffer from a progressive muscle degeneration and weakness, which lead to loss of ambulation in early teens. The pleiotropic effects of the mutant gene include non-muscle symptoms: cognitive impairment and structurally weakened bones [3, 55]. Lack of dystrophin is attributed to plasma membrane destabilization, cell signaling impairment and myofibre necrosis, accompanied by chronic sterile inflammation, and leading to irreversible replacement of muscle with fibrotic and adipose tissues [52]. Most recent studies indicated that expression of specific dystrophin isoforms is important for the proper functioning of myogenic cells [19, 72] and dystrophinopathy is responsible for the cognitive impairment and bone weakness [3, 41, 55, 59]
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