Metabolic derangements of skeletal muscle from a murine model of glioma cachexia.

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2019-01-11 DOI:10.1186/s13395-018-0188-4

Pengfei Cui, Wei Shao, Caihua Huang, Chang-Jer Wu, Bin Jiang, Donghai Lin

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引用次数: 19

Abstract

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.

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脑胶质瘤恶病质小鼠模型骨骼肌代谢紊乱。

背景:恶病质是一种复杂的代谢紊乱和肌肉萎缩综合征，影响着80%的晚期癌症患者。恶性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，胶质瘤引起的恶病质症状很少受到关注。本研究旨在探讨骨骼肌萎缩在小鼠原位胶质瘤模型中的作用。方法:BALB/c裸鼠原位植入正常胶质细胞(HEB)和胶质瘤细胞(WHO II CHG5和WHO IV U87)。通过表型、组织病理学、生理和生化分析来描述小鼠恶病质症状。western blot检测肌肉萎缩相关蛋白，并分析相关信号通路。基于核磁共振的代谢组学分析应用于骨骼肌代谢紊乱，包括多变量统计分析、特征代谢物鉴定和代谢途径分析。结果:与对照组相比，植入胶质瘤细胞的小鼠表现出典型的恶病质症状，表明与胶质瘤的恶性程度高度相关。与CHG5小鼠相比，U87小鼠出现恶病质的时间更早、更严重。胶质瘤小鼠骨骼肌质量和力量明显减少，这与抑制AKT、激活AMPK、FOXO、Atrogin1和LC3有关。有趣的是，MuRF1、MyoD1和eIF3f的表达没有明显变化。一致地，代谢组学分析阐明了病毒性腓肠肌相对于对照组明显的代谢紊乱。葡萄糖、甘油和3-羟基丁酸显著下调，而谷氨酸、精氨酸、亮氨酸和异亮氨酸在病毒性腓肠肌中上调。此外，U87小鼠表现出更多的特征性代谢产物和更多的代谢途径紊乱，包括糖脂代谢、蛋白质分解代谢、合成代谢和柠檬酸循环逆转。结论:本研究首次证明了原位胶质瘤小鼠模型在两种恶性胶质瘤中表现出高保真的恶病质表现。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提供了重要的见解，并扩大了对肌肉萎缩分子机制的理解。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.