Department of Health and Human Performance, High Point University, High Point, North Carolina, USA.
Department of Chemistry, High Point University, High Point, North Carolina, USA.
Cell Biochem Funct. 2024 Sep;42(7):e4117. doi: 10.1002/cbf.4117.
Elevated circulating branched-chain amino acids (BCAA) have been linked with the severity of insulin resistance across numerous populations, implicating heightened BCAA metabolism as a potential therapy for insulin resistance. Recently, the angiotensin II type 1 receptor (AT1R) inhibitor Valsartan (VAL) was identified as a potent inhibitor of branched-chain alpha-keto acid dehydrogenase kinase (BCKDK), a negative regulator of BCAA metabolism. This work investigated the effect of VAL on myotube metabolism and insulin sensitivity under both insulin sensitive and insulin resistant conditions. C2C12 myotubes were treated with or without VAL at 8 µM for 24 h, both with and without hyperinsulinemic-induced insulin resistance. Oxygen consumption and extracellular acidification were used to measure mitochondrial and glycolytic metabolism, respectively. Gene expression was assessed via qRT-PCR, and insulin sensitivity was assessed via Western blot. Insulin resistance significantly reduced both basal and peak mitochondrial function which were rescued to control levels by concurrent VAL. Changes in mitochondrial function occurred without substantial changes in mitochondrial content or related gene expression. Insulin sensitivity and glycolytic metabolism were unaffected by VAL, as was lipogenic signaling and lipid content. Additionally, both VAL and insulin resistance depressed Bckdha expression. Interestingly, an interaction effect was observed for extracellular isoleucine, valine, and total BCAA (but not leucine), suggesting VAL may alter BCAA utilization in an insulin sensitivity-dependent manner. Insulin resistance appears to suppress mitochondrial function in a myotube model which can be rescued by VAL. Further research will be required to explore the implications of these findings in more complex models.
循环支链氨基酸（BCAA）水平升高与许多人群的胰岛素抵抗严重程度相关，这表明升高的 BCAA 代谢可能是治疗胰岛素抵抗的一种潜在方法。最近，血管紧张素 II 型 1 型受体（AT1R）抑制剂缬沙坦（VAL）被鉴定为支链α-酮酸脱氢酶激酶（BCKDK）的有效抑制剂，BCKDK 是 BCAA 代谢的负调节剂。这项工作研究了 VAL 在胰岛素敏感和胰岛素抵抗条件下对肌管代谢和胰岛素敏感性的影响。用或不用 8 μM 的 VAL 处理 C2C12 肌管 24 小时，同时用或不用高胰岛素诱导的胰岛素抵抗。分别使用耗氧量和细胞外酸化来测量线粒体和糖酵解代谢。通过 qRT-PCR 评估基因表达，通过 Western blot 评估胰岛素敏感性。胰岛素抵抗显著降低了基础和峰值线粒体功能，而同时 VAL 则将其恢复到对照水平。线粒体功能的变化没有伴随着线粒体含量或相关基因表达的实质性变化。VAL 对胰岛素敏感性和糖酵解代谢没有影响，脂肪生成信号和脂质含量也没有影响。此外，VAL 和胰岛素抵抗均降低了 Bckdha 的表达。有趣的是，观察到细胞外异亮氨酸、缬氨酸和总 BCAA（而不是亮氨酸）的交互作用，表明 VAL 可能以胰岛素敏感性依赖的方式改变 BCAA 的利用。胰岛素抵抗似乎抑制了肌管模型中的线粒体功能，而 VAL 可以挽救这种功能。需要进一步的研究来探索这些发现在更复杂模型中的意义。
