Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance
Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance
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DOI：
10.1038/s41467-019-10712-0
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发表时间：
2019-06-24
影响因子：
16.6
通讯作者：
Ruas, Jorge L.
中科院分区：
文献类型：
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作者：
Agudelo, Leandro Z.;Ferreira, Duarte M. S.;Ruas, Jorge L.
辅激活因子PGC-1 α 1通过运动训练在骨骼肌中激活，并促进抗疲劳性。在运动的肌肉中，PGC-1 α 1增强犬尿氨酸氨基转移酶（Kats）的表达，其将犬尿氨酸转化为犬尿烯酸。这降低了犬尿氨酸相关的神经毒性，并产生谷氨酸作为副产物。在这里，我们表明，PGC-1 α 1提高天冬氨酸和谷氨酸水平，并增加糖酵解和苹果酸-天冬氨酸穿梭（MAS）基因的表达。这些相互关联的过程提高了能量利用率，并将燃料衍生的电子转移到线粒体呼吸。这种PGC-1 α 1依赖性机制允许训练的肌肉使用犬尿氨酸代谢来增加葡萄糖氧化的生物能效率。卡比多巴抑制Kat会损害小鼠的天冬氨酸生物合成、线粒体呼吸，并降低运动表现和肌肉力量。我们的研究结果表明，PGC-1 α 1激活骨骼肌中的MAS，由犬尿氨酸catalysts支持，作为耐力运动适应的一部分。犬尿氨酸代谢和MAS之间的这种串扰可能具有重要的生理和临床意义。
The coactivator PGC-1 alpha 1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1 alpha 1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1 alpha 1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1 alpha 1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1 alpha 1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.