Molecular mechanisms and putative signalling events controlling utrophin expression in mammalian skeletal muscle fibres

The absence of full-length dystrophin molecules in skeletal muscle fibres results in the most severe form of muscular dystrophy, the Duchenne form (DMD). Several years ago, an autosomal homologue to dystrophin, termed utrophin, was identified. Although utrophin is expressed along the sarcolemma in developing, regenerating and DMD muscles, it nonetheless accumulates at the postsynaptic membrane of the neuromuscular junction in both normal and DMD adult muscle fibres. Due to the high degree of sequence identity between dystrophin and utrophin, it has been previously suggested that utrophin could in fact functionally compensate for the lack of dystrophin. Recent studies using transgenic mouse model systems have directly tested this hypothesis and revealed that upregulation of utrophin throughout dystrophic muscle fibres represents indeed, a viable approach for the treatment of DMD. Current studies are therefore focusing on the elucidation of the various regulatory mechanisms presiding over expression of utrophin in muscle fibres in attempts to ultimately identify small molecules which could systematically increase utrophin levels in extrasynaptic compartments of dystrophic muscle fibres. This review presents some of the recent data relevant for our understanding of the transcriptional regulatory mechanisms involved in maintaining expression of utrophin at the neuromuscular junction. In addition, the contribution of specific cues originating from motoneurons and the putative involvement of signalling events are also discussed. (C) 1998 Elsevier Science B.V. All rights reserved.