5'-CMP and 5'-UMP alleviate dexamethasone-induced muscular atrophy in C2C12 myotubes.

Atrogin-1 and muscle RING finger 1 (MuRF1) are ubiquitin ligases specifically expressed during skeletal muscle atrophy and mediate muscle protein degradation. In contrast, PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which is a master regulator of mitochondrial biosynthesis, protects skeletal muscle from atrophy. Pyrimidine nucleoside 5'-monophosphates, such as cytidine 5'-monophosphate (5'-CMP) and uridine 5'-monophosphate (5'-UMP), induce PGC-1α expression and promote myotube formation in mouse C2C12 cells. In this study, we determined the effect of 5'-CMP and 5'-UMP on muscular atrophy in C2C12 myotube cells. 5'-UMP decreased Atrogin-1 and MuRF1 mRNA levels that were upregulated by dexamethasone treatment. 5'-CMP and 5'-UMP ameliorated dexamethasone-mediated atrophy in C2C12 myotubes. Furthermore, the combination of 5'-CMP and 5'-UMP further alleviated dexamethasone-mediated atrophy. In addition, cytidine and uridine, the precursors of 5'-CMP and 5'-UMP, markedly ameliorated dexamethasone-mediated atrophy. Considering nucleotide metabolism and absorption, the active metabolites underlying the observed effects of 5'-CMP and 5'-UMP appear to be cytidine and uridine. Our results indicate that 5'-CMP alleviates muscle atrophy by activating PGC-1α and differentiation, and 5'-UMP alleviates muscle atrophy by suppressing the activation of the myolytic system, whereas the combined use of both enhances the muscle atrophy inhibitory effect. 5'-CMP and 5'-UMP may be an effective and safe treatment for muscular atrophy.