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2017 | 77 | Suppl.1 |
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Duchenne muscular dystrophy – the slow death of a dogma

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EN
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease leading to severe disability and death of young men. The central hypothesis states that the DMD pathology results from the myofibre sarcolemma fragility due to loss of dystrophin and the main focus of pre-clinical and clinical research is on its restoration there. Unfortunately, so far no treatment improved the long-term outcome. Findings from our and other laboratories obtained using molecular and functional approaches in vitro and in vivo contradict the central hypothesis by demonstrating that loss of dystrophin in adult muscle does not necessarily triggers myofibre damage. Moreover, central to the argument presented here, we have evidence that already in myogenic cells, believed not to be affected at this stage of differentiation, DMD mutations produce significant abnormalities. These include cell proliferation, differentiation, energy metabolism, Ca2+ homeostasis and death, leading to impaired muscle regeneration. We have also shown that DMD mutations alter extracellular ATP (eATP) signalling via P2RX7 purinoceptor upregulation, leading to death of dystrophic myoblasts. Blockade of P2RX7 in the mdx mouse model of DMD produced significant improvements. As targeting signalling pathways using pharmacological agents is more achievable than restoration of structural proteins, P2RX7 is an attractive translational therapeutic target. Clearly, understanding how DMD mutations alter such a range of functions in myogenic cells is vital for developing effective therapies. We hope that starting a discussion may bring to light further results that will help re-evaluating the established belief. We have to consider whether the prevailing dogma is not steering us into a wrong direction and whether we could deliver a treatment more quickly and cheaply if alternative strategies are investigated. FINANCIAL SUPPORT: Muscular Dystrophy Association USA.
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77
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p.35-36
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  • University of Portsmouth, School of Pharmacy and Biomedical Sciences, Portsmouth, UK
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