Nakagawara Kosuke, Takeuchi Chieri, Ishige Kazuya
Biochemicals Division, YAMASA Corporation, 2-10-1 Shinseicho, Choshi, 288-0056, Japan.
Diagnostics Division, YAMASA Corporation, 2-10-1 Shinseicho, Choshi, 288-0056, Japan.
Biochem Biophys Rep. 2022 Jul 15;31:101309. doi: 10.1016/j.bbrep.2022.101309. eCollection 2022 Sep.
Ribonucleotides are basic monomeric building blocks for RNA considered as conditionally essential nutrients. They are normally produced in sufficient quantity, but can become insufficient upon stressful challenges. The administration of pyrimidine nucleotides, such as cytidine-5'-monophosphate (5'-CMP) and uridine-5'-monophosphate (5'-UMP), enables rats to endure prolonged exercise. However, the underlying mechanisms have remained elusive. To investigate these mechanisms, we studied the effect of 5'-CMP and 5'-UMP on muscular differentiation and mitochondrial biogenesis in myoblast C2C12 cells. 5'-CMP and 5'-UMP were found to increase the mRNA levels of myogenin, which is a myogenic regulatory protein expressed during the final differentiation step and fusion of myoblasts into myotubes. 5'-CMP and 5'-UMP also promoted myoblast differentiation into myotube cells. 5'-CMP and 5'-UMP further increased the mRNA levels of PGC-1α which regulates mitochondrial biogenesis and skeletal muscle fiber type. In addition, 5'-CMP and 5'-UMP increased mitochondrial DNA copy number and enhanced mRNA levels of slow-muscle myosin heavy chains. Moreover, cytidine and uridine, nucleosides corresponding to 5'-CMP and 5'-UMP, markedly promoted myotube formation in C2C12 cells. Considering the metabolism and absorption of nucleotides, the active bodies underlying the effects observed with 5'-CMP and 5'-UMP could be cytidine and uridine. In conclusion, our results indicate that 5'-CMP and 5'-UMP can promote myogenic differentiation and mitochondrial biogenesis, as well as increase slow-twitch fiber via the activation of myogenin and PGC-1α. In addition, 5'-CMP and 5'-UMP may be considered as safe and effective agents to enhance muscle growth and improve the endurance in skeletal muscles.
核糖核苷酸是RNA的基本单体组成部分，被视为条件必需营养素。它们通常能产生足够的量，但在面临压力挑战时可能会变得不足。给予嘧啶核苷酸，如5'-胞苷酸（5'-CMP）和5'-尿苷酸（5'-UMP），能使大鼠耐受长时间运动。然而，其潜在机制仍不清楚。为了研究这些机制，我们研究了5'-CMP和5'-UMP对成肌细胞C2C12细胞中肌肉分化和线粒体生物发生的影响。发现5'-CMP和5'-UMP可增加肌细胞生成素的mRNA水平，肌细胞生成素是一种在成肌细胞最终分化步骤以及融合形成肌管过程中表达的生肌调节蛋白。5'-CMP和5'-UMP还促进成肌细胞分化为肌管细胞。5'-CMP和5'-UMP进一步增加了调节线粒体生物发生和骨骼肌纤维类型的PGC-1α的mRNA水平。此外，5'-CMP和5'-UMP增加了线粒体DNA拷贝数，并提高了慢肌肌球蛋白重链的mRNA水平。此外，与5'-CMP和5'-UMP相对应的核苷胞苷和尿苷显著促进了C2C12细胞中的肌管形成。考虑到核苷酸的代谢和吸收，5'-CMP和5'-UMP产生上述作用的活性物质可能是胞苷和尿苷。总之，我们的结果表明，5'-CMP和5'-UMP可通过激活肌细胞生成素和PGC-1α来促进生肌分化和线粒体生物发生，以及增加慢肌纤维。此外，5'-CMP和5'-UMP可被视为增强肌肉生长和提高骨骼肌耐力的安全有效药物。
