MOLECULAR BASIS OF THE THERAPEUTIC EFFECT OF NITRIC OXIDE AND THE NITRIC OXIDE-RELEASING ANTI-INFLAMMATORY DRUG NITROFLURBIPROFEN IN MUSCULAR DYSTROPHY: ANALYSIS OF MITOCHONDRIAL STRUCTURE AND FUNCTION IN DEVELOPING AND REGENERATING SKELETAL MUSCLE

A resolutive therapy for the Duchenne Muscular Dystrophy is not yet available. The use of corticosteroids, to control inflammation and slow disease progression, causes severe side effects with limited clinical benefits. We found that a new class of compounds that combine anti-inflammatory actions with the properties of nitric oxide (NO-NSAIDS) have therapeutic efficacy in mouse models of dystrophy. These compounds can be delivered orally without detectable side effects, and appear therefore ideal candidates for a new safer and effective therapy of muscular dystrophy. Optimisation of this therapy also through the elucidation of the molecular basis of the efficacy of NO-NSAIDS is a prerequisite for clinical testing of these compounds. Our preliminary results show that regulation of myogenesis contributes significantly to the therapeutic action of NO-NSAIDS, in a process that involves tight regulation of structure and function of mitochondria, the powerhouses of muscle fibres. NO-NSAIDS appear to act by regulating the function of DRP-1 a protein involved in mitochondrial structure determination. We will characterise the role of nitroflurbiprofen as a prototype NO-NSAID in embryonic and adult myogenesis with focus on changes in mitochondrial structure and function. Studies will be carried out in vivo, using chick and mouse models of dystrophy, and in vitro. The role of mitochondrial dynamics and their control by NO will be further assessed in vivo using transgenic mice over-expressing DRP-1. Anticipated output Elucidating the molecular basis of the therapeutic action of NO-NSAIDS may help refining NO-based therapies, pave the way to clinical trials and shed light on additional processes that may become target of new effective therapies of muscular dystrophy.