Miranda-Cervantes Adriana, Fritzen Andreas M, Raun Steffen H, Hodek Ondřej, Møller Lisbeth L V, Johann Kornelia, Deisen Luisa, Gregorevic Paul, Gudiksen Anders, Artati Anna, Adamski Jerzy, Andersen Nicoline R, Sigvardsen Casper M, Carl Christian S, Voldstedlund Christian T, Kjøbsted Rasmus, Hauck Stefanie M, Schjerling Peter, Jensen Thomas E, Cebrian-Serrano Alberto, Jähnert Markus, Gottmann Pascal, Burtscher Ingo, Lickert Heiko, Pilegaard Henriette, Schürmann Annette, Tschöp Matthias H, Moritz Thomas, Müller Timo D, Sylow Lykke, Kiens Bente, Richter Erik A, Kleinert Maximilian
Department of Molecular Physiology of Exercise and Nutrition, German Institute of Human Nutrition (DIfE), Potsdam-Rehbruecke, Nuthetal, Germany.
German Center for Diabetes Research (DZD), Munich, Germany.
Nat Commun. 2025 Jan 2;16(1):345. doi: 10.1038/s41467-024-55036-w.
Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.
骨骼肌中的代谢灵活性对于维持健康的葡萄糖和脂质代谢至关重要，其功能障碍与代谢性疾病密切相关。运动可增强代谢灵活性，使其成为发现促进代谢健康机制的重要工具。在此我们表明，泛酸激酶4（PanK4）是肌肉中高丰度的一个新的保守运动靶点。肌肉特异性缺失PanK4会损害脂肪酸氧化，这与肌肉内较高的乙酰辅酶A和丙二酰辅酶A水平有关。无论进食状态如何，乙酰辅酶A水平都会持续升高，并与全身葡萄糖不耐受、糖酵解肌肉中胰岛素刺激的葡萄糖摄取减少以及运动期间的葡萄糖摄取受损有关。相反，增加糖酵解肌肉中的PanK4水平可降低乙酰辅酶A并增强葡萄糖摄取。我们的研究结果突出了PanK4作为乙酰辅酶A水平的重要调节因子，在肌肉脂质和葡萄糖代谢中均发挥关键作用。
