Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Sci Rep. 2020 Feb 5;10(1):1908. doi: 10.1038/s41598-020-58213-1.
Perturbations in skeletal muscle metabolism have been reported for a variety of neuromuscular diseases. However, the role of metabolism after constriction injury to a nerve and the associated muscle atrophy is unclear. We have analyzed rat tibialis anterior (TA) four weeks after unilateral constriction injury to the sciatic nerve (DMG) and in the contralateral control leg (CTRL) (n = 7) to investigate changes of the metabolome, immunohistochemistry and protein levels. Untargeted metabolomics identified 79 polar metabolites, 27 of which were significantly altered in DMG compared to CTRL. Glucose concentrations were increased 2.6-fold in DMG, while glucose 6-phosphate (G6-P) was unchanged. Intermediates of the polyol pathway were increased in DMG, particularly fructose (1.7-fold). GLUT4 localization was scattered as opposed to clearly at the sarcolemma. Despite the altered localization, we found GLUT4 protein levels to be increased 7.8-fold while GLUT1 was decreased 1.7-fold in nerve damaged TA. PFK1 and GS levels were both decreased 2.1-fold, indicating an inability of glycolysis and glycogen synthesis to process glucose at sufficient rates. In conclusion, chronic nerve constriction causes increased GLUT4 levels in conjunction with decreased glycolytic activity and glycogen storage in skeletal muscle, resulting in accumulation of intramuscular glucose and polyol pathway intermediates.
多种神经肌肉疾病都报道了骨骼肌代谢紊乱。然而，神经缩窄损伤后代谢的变化及其相关的肌肉萎缩的机制仍不清楚。我们分析了单侧坐骨神经缩窄损伤（DMG）后 4 周的大鼠比目鱼肌（TA）和对侧对照（CTRL）腿（n=7），以研究代谢组、免疫组织化学和蛋白水平的变化。非靶向代谢组学鉴定了 79 个极性代谢物，其中 27 个在 DMG 中与 CTRL 相比有显著变化。DMG 中的葡萄糖浓度增加了 2.6 倍，而葡萄糖 6-磷酸（G6-P）不变。多元醇途径的中间产物在 DMG 中增加，特别是果糖（增加 1.7 倍）。GLUT4 定位呈散射状，而不是清晰地位于肌膜上。尽管定位发生了改变，我们发现神经损伤的 TA 中的 GLUT4 蛋白水平增加了 7.8 倍，而 GLUT1 减少了 1.7 倍。PFK1 和 GS 水平均下降 2.1 倍，表明糖酵解和糖原合成无法以足够的速度处理葡萄糖。总之，慢性神经缩窄导致 GLUT4 水平升高，同时糖酵解活性和肌肉糖原储存降低，导致肌肉内葡萄糖和多元醇途径中间产物堆积。
