Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
Food Funct. 2024 Apr 22;15(8):4389-4398. doi: 10.1039/d3fo04174c.
β-Hydroxy-β-methylbutyrate (HMB) is a breakdown product of leucine, which promotes muscle growth. Although some studies indicate that HMB activates AKT and mTOR, others show activation of the downstream effectors, P70S6K and S6, independent of mTOR. Our aim was to study the metabolic effect of HMB around the circadian clock in order to determine more accurately the signaling pathway involved. C2C12 myotubes were treated with HMB and clock, metabolic and myogenic markers were measured around the clock. HMB-treated C2C12 myotubes showed no activation of AKT and mTOR, but did show activation of P70S6K and S6. Activation of P70S6K and S6 was also found when myotubes were treated with HMB combined with metformin, an indirect mTOR inhibitor, or rapamycin, a direct mTOR inhibitor. The activation of the P70S6K and S6 independent of AKT and mTOR, was accompanied by increased activation of phospholipase D2 (PLD). In addition, HMB led to high amplitude and advanced circadian rhythms. In conclusion, HMB induces myogenesis in C2C12 by activating P70S6K and S6 PLD2, rather than AKT and mTOR, leading to high amplitude advanced rhythms.
β-羟基-β-甲基丁酸（HMB）是亮氨酸的分解产物，可促进肌肉生长。虽然一些研究表明 HMB 能激活 AKT 和 mTOR，但其他研究表明，下游效应物 P70S6K 和 S6 的激活与 mTOR 无关。我们的目的是研究 HMB 在生物钟周围的代谢作用，以便更准确地确定所涉及的信号通路。用 HMB 和时钟处理 C2C12 肌管，在生物钟周围测量代谢和肌生成标记物。用 HMB 处理的 C2C12 肌管没有激活 AKT 和 mTOR，但确实激活了 P70S6K 和 S6。当肌管与二甲双胍（间接 mTOR 抑制剂）或雷帕霉素（直接 mTOR 抑制剂）联合用 HMB 处理时，也发现了 P70S6K 和 S6 的激活。这种不依赖于 AKT 和 mTOR 的 P70S6K 和 S6 的激活伴随着磷脂酶 D2（PLD）的激活增加。此外，HMB 导致节律振幅增大和节律提前。总之，HMB 通过激活 P70S6K 和 S6-PLD2 而不是 AKT 和 mTOR 诱导 C2C12 的肌生成，从而导致振幅增大和节律提前。
