Skeletal muscle is heterogeneous tissue, composed of fast-twitch fibers primarily relying on glycolysis and slow-twitch fibers primarily relying on oxidative phosphorylation. The relative expression and balance of glycolysis and oxidative phosphorylation in skeletal muscle are crucial for muscle growth and skeletal muscle metabolism. Here, we employed multi-omics approaches including transcriptomics, proteomics, phosphoproteomics, and metabolomics to unravel the role of circMYLK4, a differentially expressed circRNA in fast and slow-twitch muscle fibers, in muscle fiber metabolism. We discovered that circMYLK4 inhibits glycolysis and promotes mitochondrial oxidative phosphorylation. Mechanistically, circMYLK4 interacts with the voltage-gated calcium channel auxiliary subunit CACNA2D2, leading to the inhibition of Ca release from the sarcoplasmic reticulum. The decrease in cytoplasmic Ca concentration inhibits the expression of key enzymes, PHKB and PHKG1, involved in glycogen breakdown, thereby suppressing glycolysis. On the other hand, the increased fatty acid β-oxidation enhances the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation. In general, circMYLK4 plays an indispensable role in maintaining the metabolic homeostasis of skeletal muscle.

中文翻译：

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环状RNA circMYLK4通过与钙通道辅助亚基CACNA2D2结合将能量代谢从糖酵解转变为OXPHOS


骨骼肌是异质组织，由主要依靠糖酵解的快肌纤维和主要依靠氧化磷酸化的慢肌纤维组成。骨骼肌中糖酵解和氧化磷酸化的相对表达和平衡对于肌肉生长和骨骼肌代谢至关重要。在这里，我们采用转录组学、蛋白质组学、磷酸化蛋白质组学和代谢组学等多组学方法来揭示 circMYLK4（一种在快肌纤维和慢肌纤维中差异表达的 circRNA）在肌纤维代谢中的作用。我们发现 circMYLK4 抑制糖酵解并促进线粒体氧化磷酸化。从机制上讲，circMYLK4 与电压门控钙通道辅助亚基 CACNA2D2 相互作用，导致肌浆​​网 Ca 释放受到抑制。细胞质 Ca 浓度的降低抑制参与糖原分解的关键酶 PHKB 和 PHKG1 的表达，从而抑制糖酵解。另一方面，脂肪酸β-氧化的增加增强了三羧酸循环和线粒体氧化磷酸化。一般来说，circMYLK4在维持骨骼肌的代谢稳态中发挥着不可或缺的作用。