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Abstract：
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 Ca2+ release from the sarcoplasmic reticulum. The decrease in cytoplasmic Ca2+ 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.
摘要：
骨骼肌是异质组织，由主要依靠糖酵解的快速抽搐纤维和主要依靠氧化磷酸化（OXPHOS）的缓慢抽搐纤维组成。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。这里,我们采用了多组学方法，包括转录组学，蛋白质组学，磷酸蛋白质组学，和代谢组学来解开circMYLK4的作用，circLK4是一种在快速和慢速抽搐肌纤维中差异表达的circRNA，在肌肉纤维代谢中。我们发现circMYLK4抑制糖酵解并促进线粒体氧化磷酸化。机械上,circMYLK4与电压门控钙通道辅助亚基CACNA2D2相互作用，导致抑制肌浆网释放Ca2。细胞质Ca2+浓度的降低抑制了关键酶的表达,PHKB和PHKG1，参与糖原分解，从而抑制糖酵解。另一方面,增加的脂肪酸β-氧化增强三羧酸(TCA)循环和线粒体氧化磷酸化。总的来说,circMYLK4在维持骨骼肌的代谢稳态中起着不可或缺的作用。
