Diaphragm‐specific effects of L‐citrulline in <i>mdx</i> mice highlight its potential as adjuvant of standard therapy in Duchenne muscular dystrophy

BACKGROUND AND PURPOSE: The absence of the protein dystrophin in Duchenne muscular dystrophy (DMD) leads to progressive muscle weakness, failing regeneration and deregulation of nitric oxide (NO) signalling. We focused on L-citrulline, a precursor of L-arginine, required for NO production in muscle, which is reduced in dystrophic mdx muscle. EXPERIMENTAL APPROACH: , 5 days per week subcutaneously) to 4- to 5-week-old mdx mice for 8 weeks. KEY RESULTS: handling during contraction (RyR1, RyR3 and SERCA), while reducing the markers of inflammation and fibrosis (CD68 and TGFβ1) and ameliorating mitochondrial biogenesis-associated genes (PGC1-α and MEF2C). No effect was observed on S-nitrosylation levels of HDAC2 and on diaphragm and gastrocnemius nNOS gene expression, suggesting a NO-independent mechanism underlying the positive outcome observed. CONCLUSIONS: Our results revealed the ability of L-citrulline supplementation to ameliorate in vivo and ex vivo function of diaphragm muscle, highlighting novel metabolic and calcium-related mechanisms of potential clinical interest.