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Dietary L-citrulline is thought to modulate muscle protein turnover by increasing L-arginine availability. To date, the direct effects of increased L-citrulline concentrations in muscle have been completely neglected. Therefore, we determined the role of L-citrulline in regulating cell size during catabolic conditions by depriving mature C2C12 myotubes of growth factors (serum free; SF) or growth factors and nutrients (HEPES buffered saline; HBS). Cells were treated with L-citrulline or equimolar concentrations of L-arginine (positive control) or L-alanine (negative control) and changes in cell size and protein turnover were assessed. In myotubes incubated in HBS or SF media, L-citrulline improved rates of protein synthesis (HBS: +63%, SF: +37%) and myotube diameter (HBS: +18%, SF: +29%). L-citrulline treatment substantially increased  iNOS  mRNA expression (SF: 350%, HBS: 750%). The general NOS inhibitor L-NAME and the  iNOS  specific inhibitor aminoguanidine prevented these effects in both models. Depriving myotubes in SF media of L-arginine or L-leucine, exacerbated wasting which was not attenuated by L-citrulline. The increased  iNOS  mRNA expression was temporally associated with increases in mRNA of the endogenous antioxidants  SOD1 ,  SOD3  and  catalase . Furthermore, L-citrulline prevented inflammation (LPS) and oxidative stress (H 2 O 2 ) induced muscle cell wasting. In conclusion, we demonstrate a novel direct protective effect of L-citrulline on skeletal muscle cell size independent of L-arginine that is mediated through induction of the inducible NOS ( iNOS ) isoform. This discovery of a nutritional modulator of  iNOS  mRNA expression in skeletal muscle cells could have substantial implications for the treatment of muscle wasting conditions.

L-Citrulline Protects Skeletal Muscle Cells from Cachectic Stimuli through an iNOS-Dependent Mechanism