Résumé :
|
Communication n° 572 The ion-channel subunit P2X2 is one of seven known subunits forming homomeric and heteromeric receptors for ATP. This receptor subunit is expressed in developing mammalian skeletal muscle, but not in adult muscle fibres. The timing of P2X2 receptor expression is related to the development of the mature innervation pattern in skeletal muscle and it is known that significant quantities of ATP are co-released with acetylcholine from motor nerve terminals. Thus, the aim of this study was to investigate the role of P2X2 receptor expression in mammalian skeletal muscle development using the P2X2-/- mouse. We show that adult P2X2-/- mice have abnormalities in neuromuscular junction (NMJ) structure and in skeletal muscle function. Whereas normal NMJs are characterised by the precise apposition of pre-synaptic motor nerve terminals and post-synaptic junctional folds rich in AChRs, NMJs in P2X2-/- mice were disorganised: mis-apposition of nerve terminals and areas of high AChR expression was common in knockout NMJs; there were significantly fewer post-synaptic junctional folds, and there was increased end-plate fragmentation. These changes in NMJ structure were associated with reduced muscle strength, a decrease in the average muscle fibre cross-sectional area and an increase in the percentage of fast (type II) muscle fibres in soleus muscle. Furthermore, while sciatic nerve crush experiments conducted on P2X2 wild-type and knockout mice demonstrated similar recovery of muscle innervation following injury, there was evidence of delayed recovery of NMJ structure in P2X2-deificent mice. Whereas NMJs in wild-type mice had largely returned to normal three weeks after injury, structural abnormalities in the NMJs in P2X2-deficient mice were apparent. These findings suggest that absence of the P2X2 receptor results in functional, but improperly formed NMJs, leading to abnormalities in skeletal muscle strength, muscle fibre type and a reduced ability to respond to injury.
|