Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
J Biol Chem. 2024 Jul;300(7):107426. doi: 10.1016/j.jbc.2024.107426. Epub 2024 May 30.
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.
骨骼肌是一种异质组织，由主要依赖糖酵解的快肌纤维和主要依赖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肌肉生长和骨骼肌代谢至关重要。在这里，我们采用了包括转录组学、蛋白质组学、磷酸化蛋白质组学和代谢组学在内的多组学方法，揭示了差异表达于快肌和慢肌纤维中的 circMYLK4 在肌肉纤维代谢中的作用。我们发现 circMYLK4 抑制糖酵解并促进线粒体氧化磷酸化。在机制上，circMYLK4 与电压门控钙通道辅助亚基 CACNA2D2 相互作用，导致肌浆网中 Ca 的释放受到抑制。细胞质中 Ca 浓度的降低抑制了糖原分解中关键酶 PHKB 和 PHKG1 的表达，从而抑制糖酵解。另一方面，增加的脂肪酸 β-氧化增强了三羧酸循环和线粒体氧化磷酸化。总的来说，circMYLK4 在维持骨骼肌代谢平衡中起着不可或缺的作用。
