PO.MCB09.01 · 分子与细胞生物学
乳腺癌（BC）小鼠模型中癌症相关性疲劳（CRF）背后的代谢与炎症交互作用
Metabolic and inflammatory crosstalk underlying cancer-related fatigue (CRF) in a mouse model of breast cancer (BC)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症相关性疲劳（CRF）是女性乳腺癌及其治疗中最普遍且最使人衰弱的副作用之一，严重降低治疗依从性和生活质量。然而，标准化的临床前CRF评价指标仍界定不清，阻碍了治疗性干预措施的开发。我们假设乳腺癌诱导的躯体疲劳源于骨骼肌线粒体的代谢失调。我们采用同基因型E0771乳腺癌小鼠模型，对躯体疲劳进行了表征，评估了细胞因子谱，并对肌肉进行了靶向代谢组学分析。荷瘤小鼠的生存期显著缩短、脂肪量减少，尽管总体重和瘦体重保持稳定。肿瘤生长三周后，躯体运动能力下降，表现为握力、最大速度和峰值耗氧量降低。小鼠的代谢笼活动显示耗氧量、二氧化碳产生量、呼吸交换率、能量消耗和饮水量均降低，与代谢功能受抑制一致。骨骼肌代谢组学分析显示，与氨基酸代谢和氧化应激信号相关的代谢物哌可酸（pipecolate）和吡哆胺（pyridoxamine）上调，而包括谷胱甘肽、核黄素和异柠檬酸在内的关键线粒体和抗氧化代谢物受到抑制。这些改变提示线粒体功能障碍、氧化还原失衡和能量产生受损是躯体疲劳表型的诱因。这些变化伴随血浆中IL1beta、IL-2、MIP-1alpha降低和IP-10升高，提示炎症驱动的代谢重编程。乳腺癌在骨骼肌中诱导了协调一致的炎症和代谢变化，破坏了促成躯体疲劳的线粒体通路。本研究确定了与CRF相关的独特代谢特征，并强调线粒体通路是改善乳腺癌患者生活质量的有前景的治疗干预靶点。
查看英文原文 English abstract
Cancer-related fatigue (CRF) is among the most prevalent and debilitating side effects of breast cancer and its treatment in women, severely reducing adherence to treatment and quality of life. However, standardized, preclinical metrics for CRF remain poorly defined, impeding the development of therapeutic interventions. We hypothesized that breast cancer-induced physical fatigue is due to metabolic dysregulation in skeletal muscle mitochondria. Using the syngeneic E0771 mouse model of breast cancer, we characterized physical fatigue, assessed cytokine profiles, and performed targeted metabolomic analyses of muscle. Tumor-bearing mice showed significantly reduced survival and fat mass although overall body weight and lean mass were stable. Physical performance declined after three weeks of tumor growth as shown by reduced grip strength, maximum speed and peak oxygen consumption. Metabolic cage activity of mice revealed reduced oxygen consumption, carbon dioxide production, respiratory exchange ratio, energy expenditure, and water intake, consistent with suppressed metabolic function. Metabolomic profiling of skeletal muscle revealed upregulation of pipecolate and pyridoxamine, metabolites linked to amino acid metabolism and oxidative stress signaling, while key mitochondrial and antioxidant metabolites including glutathione, riboflavin and isocitrate were suppressed. These alterations suggest mitochondrial dysfunction, redox imbalance, and impaired energy production as contributors to the physical fatigue phenotype. These changes were accompanied by reduced IL1beta, IL-2, MIP-1alpha and increased IP-10 in the plasma implicating inflammation-driven metabolic reprogramming. Breast cancer induced coordinated inflammatory and metabolic changes in the skeletal muscle, disrupting mitochondrial pathways that contribute to physical fatigue. This study identifies distinct metabolic signatures associated with CRF and highlights mitochondrial pathways as promising targets for therapeutic intervention to improve the quality of life in breast cancer patients.
利益披露 Disclosure
A. A. Koomson, None..
S. C. B. Nakandakari, None..
A. Fosam, None..
R. M. Grijalva, None.