BACKGROUND Cachexia is a complex metabolic disorder and muscle atrophy syndrome, impacting 80% patients with advanced cancers. Malignant glioma is considered to be one of the deadliest human cancers, accounting for about 60% of all primary brain tumors. However, cachexia symptoms induced by glioma have received little attention. This work aims to explore skeletal muscle atrophy in orthotopic glioma murine models. METHODS BALB/c nude mice were orthotopicly implanted with normal glial (HEB) and glioma (WHO II CHG5 and WHO IV U87) cells. Cachexia symptoms of mice were depicted by phenotypic, histopathologic, physiological, and biochemical analyses. Muscle atrophy-related proteins were examined by western blot, and the involved signaling pathways were analyzed. NMR-based metabolomic analysis was applied to profile metabolic derangements in the skeletal muscle, including multivariate statistical analysis, characteristic metabolite identification, and metabolic pathway analysis. RESULTS Compared with controls, mice implanted with glioma cells exhibit typical cachexia symptoms, indicating a high correlation with the malignant grades of glioma. U87 mice develop cachexia much earlier and more severe than CHG5 mice. The glioma-bearing mice showed significantly decreased skeletal muscle mass and strength, which were associated with suppressed AKT, activated AMPK, FOXO, Atrogin1, and LC3. Interestingly, expressions of MuRF1, MyoD1, and eIF3f were not significantly changed. Consistently, metabolomic analyses elucidate pronounced metabolic derangements in cachectic gastrocnemius relative to controls. Glucose, glycerol, and 3-hydroxybutyrate were remarkably downregulated, whereas glutamate, arginine, leucine, and isoleucine were upregulated in cachectic gastrocnemius. Furthermore, U87 mice showed more characteristic metabolites and more disturbed metabolic pathways including glucose and lipid metabolism, protein catabolism, anabolism, and citric acid cycle anaplerotic. CONCLUSIONS This study demonstrates for the first time that the orthotopic glioma murine model developed here exhibits high fidelity of cachexia manifestations in two malignant grades of glioma. Signaling pathway analysis in combination with metabolomic analysis provides significant insights into the complex pathophysiology of glioma cachexia and expands understanding of the molecular mechanisms underlying muscle atrophy.

中文翻译：

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胶质瘤恶病质小鼠模型的骨骼肌代谢紊乱。

背景技术恶病质是一种复杂的代谢紊乱和肌肉萎缩综合征，影响了80％的晚期癌症患者。恶性神经胶质瘤被认为是最致命的人类癌症之一，约占所有原发性脑肿瘤的60％。然而，由神经胶质瘤引起的恶病质症状很少受到关注。这项工作旨在探索原位神经胶质瘤小鼠模型中的骨骼肌萎缩。方法向BALB / c裸鼠原位植入正常神经胶质细胞（HEB）和神经胶质瘤（WHO II CHG5和WHO IV U87）细胞。通过表型，组织病理学，生理学和生化分析来描述小鼠的恶病质症状。肌肉萎缩相关蛋白通过蛋白质印迹法检查，并分析了涉及的信号通路。基于NMR的代谢组学分析被用于分析骨骼肌中的代谢紊乱，包括多变量统计分析，特征性代谢物鉴定和代谢途径分析。结果与对照组相比，植入神经胶质瘤细胞的小鼠表现出典型的恶病质症状，表明与恶性神经胶质瘤的高度相关。与CHG5小鼠相比，U87小鼠更容易发生恶病质，并且发展更为严重。患有神经胶质瘤的小鼠显示骨骼肌质量和强度明显下降，这与抑制AKT，激活的AMPK，FOXO，Atrogin1和LC3有关。有趣的是，MuRF1，MyoD1和eIF3f的表达没有明显改变。一致地，代谢组学分析阐明了恶病质腓肠肌相对于对照的明显的代谢紊乱。葡萄糖，甘油和3-羟基丁酸酯显着下调，而谷氨酸，精氨酸，亮氨酸和异亮氨酸在恶病质腓肠肌中被上调。此外，U87小鼠表现出更多的特征性代谢产物和更多受干扰的代谢途径，包括葡萄糖和脂质代谢，蛋白质分解代谢，合成代谢和柠檬酸循环过失。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两个恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见解，并扩大了对肌肉萎缩的分子机制的了解。而在恶病质腓肠肌中谷氨酸，精氨酸，亮氨酸和异亮氨酸被上调。此外，U87小鼠表现出更多的特征性代谢产物和更多受干扰的代谢途径，包括葡萄糖和脂质代谢，蛋白质分解代谢，合成代谢和柠檬酸循环过失。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两个恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见识，并扩大了对肌肉萎缩的分子机制的了解。而在恶病质腓肠肌中谷氨酸，精氨酸，亮氨酸和异亮氨酸被上调。此外，U87小鼠表现出更多的特征性代谢产物和更多受干扰的代谢途径，包括葡萄糖和脂质代谢，蛋白质分解代谢，合成代谢和柠檬酸循环过失。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两个恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见识，并扩大了对肌肉萎缩的分子机制的了解。U87小鼠表现出更多的特征性代谢产物和更多受干扰的代谢途径，包括葡萄糖和脂质代谢，蛋白质分解代谢，合成代谢和柠檬酸循环过失。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两种恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见识，并扩大了对肌肉萎缩的分子机制的了解。U87小鼠表现出更多的特征性代谢产物和更多受干扰的代谢途径，包括葡萄糖和脂质代谢，蛋白质分解代谢，合成代谢和柠檬酸循环过失。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两个恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见识，并扩大了对肌肉萎缩的分子机制的了解。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两个恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见识，并扩大了对肌肉萎缩的分子机制的了解。结论这项研究首次证明，这里开发的原位神经胶质瘤鼠模型在两个恶性神经胶质瘤中均表现出较高的保真度。信号通路分析与代谢组学分析相结合，为神经胶质瘤恶病质的复杂病理生理学提供了重要见识，并扩大了对肌肉萎缩的分子机制的了解。