title: Dystrophin: The dead calm of a dogma.
abstract: Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease leading to severe disability and death of young men. Current interventions are palliative as no treatment improves the long-term outcome. Therefore, new therapeutic modalities with translational potential are urgently needed and abnormalities downstream from the absence of dystrophin are realistic targets. It has been shown that DMD mutations alter extracellular ATP (eATP) signaling via P2RX7 purinoceptor upregulation, which leads to autophagic death of dystrophic muscle cells. Furthermore, the eATP-P2RX7 axis contributes to DMD pathology by stimulating harmful inflammatory responses. We demonstrated recently that genetic ablation or pharmacological inhibition of P2RX7 in the mdx mouse model of DMD produced functional attenuation of both muscle and non-muscle symptoms, establishing this receptor as an attractive therapeutic target. Central to the argument presented here, this purinergic phenotype affects dystrophic myoblasts. Muscle cells were believed not to be affected at this stage of differentiation, as they do not produce detectable dystrophin protein. Our findings contradict the central hypothesis stating that aberrant dystrophin expression is inconsequential in myoblasts and the DMD pathology results from effects such as sarcolemma fragility, due to the absence of dystrophin, in differentiated myofibres. However, we discuss here the evidence that, already in myogenic cells, DMD mutations produce a plethora of abnormalities, including in cell proliferation, differentiation, energy metabolism, Ca(2+) homeostasis and death, leading to impaired muscle regeneration. We hope that this discussion may bring to light further results that will help re-evaluating the established belief. Clearly, understanding how DMD mutations alter such a range of functions in myogenic cells is vital for developing effective therapies.
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth , Portsmouth, UK.
authors.forename: Dariusz C
authors.initials: DC
authors.lastname: Górecki
keywords: ATP; Duchenne muscular dystrophy; P2RX7; mdx; myoblast