Expression of full-length utrophin prevents muscular dystrophy in mdx mice

Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting d isease caused by a loss of sarcolemmal bound dystrophin, which results in t he death of the muscle fiber leading to the gradual depletion of skeletal m uscle(1). The molecular structure of dystrophin is very similar to that of the related protein utrophin(2). Utrophin is found in all tissues(3) and is confined to the neuromuscular and myotendinous junctions in mature muscle( 4). Sarcolemmal localization of a truncated utrophin transgene in the dystr ophin-deficient mdx mouse significantly improves the dystrophic muscle phen otype(5,6). Therefore, upregulation of utrophin by drug therapy is a plausi ble therapeutic approach in the treatment of DMD. Here we demonstrate that expression of full-length utrophin in mdx mice prevents the development of muscular dystrophy. We assessed muscle morphology, fiber regeneration and m echanical properties (force development and resistance to stretch) of mdx a nd transgenic mdx skeletal and diaphragm muscle. The utrophin levels requir ed in muscle are significantly less than the normal endogenous utrophin lev els seen in lung and kidney, and we provide evidence that the pathology dep ends on the amount of utrophin expression. These results also have importan t implications for DMD therapies in which utrophin replacement is achieved by delivery using exogenous vectors.