Utrophin regulation in muscle

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by alterations of dystrophin gene. Patients proceed toward a progressive degeneration of muscle for the lack of dystrophin, a protein with structural role in skeletal muscle. At the moment there is no cure for DMD and BMD but are under investigation two possible therapeutic approaches. The first consists in the introduction of a 'normal' dystrophin gene into muscle cells of patients using viral vectors which, due to the low efficiency of gene delivery and the abundance of the muscle tissue, it could take a long time to develop. The second takes advantage on the presence in the human genome of another gene highly related to dystrophin that codes for a protein named utrophin. Utrophin and dystrophin are highly similar and play similar roles in muscle. In mice it has been shown that utrophin can substitute for dystrophin functionally. The expression of high levels utrophin in muscles where the dystrophin gene is altered will be able to cure muscle dystrophy. In adult muscles utrophin is minimally expressed while it naturally 'substitutes' dystrophin in foetal life and during muscle regeneration after injury. This goal will be achieved once the utrophin inducers are known. In our laboratory the research is focused on studying utrophin gene regulation to find which are the regulators that permit to switch on the utrophin gene in muscle. In the past years we have identified utrophin regulatory elements on the gene and some key molecules that activate utrophin in muscle cells. The work in progress aims at the identification of the key molecules that induce the utrophin gene in adult muscles using as a model the naturally occurring activation of utrophin during muscle recovery after injury. The results of our research will provide new molecular targets to develop specific pharmacological substances aimed at the up-regulation of the utrophin gene for the cure of DMD and BMD.