VP.86 Effect of a chronic treatment with L-citrulline on funtional, histological and molecular readouts of dystrophic mdx mouse model

Abstract

The absence of protein dystrophin in Duchenne muscular dystrophy leads to progressive muscle weakness and wasting, paralleled by failing regeneration. Recently, a key role of deregulated nitric oxide production in epigenetic control of regeneration program has been demonstrated. We focused on the potential interest of the amino acid L-citrulline (L-Cit), a precursor of L-arginine, physiologically required for protein turnover and nitric oxide production in muscle and blood vessels. We administered L-citrulline (2 mg/g/die), through diet, alone or in combination with PDN, (1 mg/kg, 5 days/week subcutaneously) to 4-5 week-old mdx mice for 8 weeks. We found that the increment of maximal forelimb strength was improved in all treated groups vs. untreated mdx mice, particularly by L-Cit alone or with PDN. Ex vivo, treated mdx mice displayed a significant increase of specific isometric twitch and tetanic force in diaphragm (DIA), with minor effects in extensor digitorum longus muscle. Additionally, L-Cit, alone or in combination with PDN, reduced fibrosis and inflammation in gastrocnemius and DIA muscles, and decreased plasma levels of lactate dehydrogenase. PCR analysis in muscles is currently ongoing. These data are encouraging regarding the potential benefits of L-Cit supplementation in DMD also in combination with standard therapy (NL-DPP grant).