Muscle function and depression-like behavior in a mouse model of cancer fatigue

描述（由申请人提供）：许多患有持续性肿瘤疾病的癌症幸存者患有癌症相关疲劳（CRF），通常伴有抑郁情绪和肌肉无力。越来越多的证据表明，癌症患者的疲劳和抑郁与血浆促炎细胞因子水平升高有关。这些细胞因子具有与理解CRF症状相关的多靶器官作用。在肌肉中，它们抑制肌肉生成，引起自噬和肌球蛋白的降解，导致肌肉质量的损失和收缩力的降低。在大脑中，细胞因子增加一种酶的表达，这种酶可以减少血清素的合成，血清素是一种参与调节情绪和运动活动的神经递质，并增加其他色氨酸代谢物的合成，这些代谢物具有神经抑制作用，与抑郁情绪有关。本项目的目的是了解细胞因子在CRF动物模型中引起抑郁情绪和骨骼肌萎缩的分子通路中的作用及其相互作用。目的1是在荷瘤小鼠中测试细胞因子、肌肉萎缩生物标志物和抑郁之间的因果关系，其中疲劳模型为自愿轮式跑步活动减少（VWRA），抑郁情绪模型为快感缺乏，对糖水的偏好减少。用二甲胺四环素治疗荷瘤小鼠，降低细胞因子的表达；布洛芬降低tnfa诱导骨骼肌萎缩的下游介质的活性；氟西汀，一种选择性血清素再摄取抑制剂（SSRI），或1-甲基色氨酸，一种色氨酸代谢的竞争性拮抗剂。目的二是确定不运动是否会夸大肿瘤生长对自由运动小鼠和久坐小鼠肌肉功能和情绪的影响。肌肉功能测试将包括总肌凝蛋白和肌凝蛋白异构体、收缩特性和肌肉再生、自噬和肌凝蛋白降解的生物标志物。该项目的研究结果将增加我们对疲劳和抑郁机制的理解，这将为更有效的治疗方法提供信息，以降低CRF并改善患有持续性肿瘤疾病的癌症幸存者的功能状态。

DESCRIPTION (provided by applicant): Many cancer survivors with persistent tumor disease suffer from cancer-related fatigue (CRF), which is often accompanied by depressed mood and muscle weakness. Mounting evidence indicates that fatigue and depression in cancer patients are associated with elevated plasma levels of pro-inflammatory cytokines. These cytokines have multiple target organ effects relevant to understanding the symptoms of CRF. In muscle, they suppress myogenesis and cause autophagy and degradation of myosin, resulting in loss of muscle mass and reduced contraction force. In the brain, cytokines increase expression of an enzyme which reduces synthesis of serotonin, a neurotransmitter involved in regulation of mood and locomotor activity, and increase synthesis of other tryptophan metabolites with neurodepressive effects and are associated with depressed mood. The goal of this project is to understand the effects of cytokines on the molecular pathways causing depressed mood and skeletal muscle wasting and their interaction in an animal model of CRF. Aim 1 is to test cause-and-effect relationships between cytokines, biomarkers of muscle wasting and depression in tumor-bearing mice in which fatigue is modeled as reduced voluntary wheel running activity (VWRA) and depressed mood is modeled as anhedonia, a reduced preference for sugar water. Tumor-bearing mice will be treated with minocycline to reduce cytokine expression; ibuprofen to reduce the activity of a downstream mediator of TNFa-induced skeletal muscle wasting; fluoxetine, a selective serotonin reuptake inhibitor (SSRI) , or 1-methyl tryptophan, a competitive antagonist of tryptophan metabolism. Aim 2 is to determine if physical inactivity exaggerates the effects of tumor growth on muscle function and mood in freely running versus sedentary tumor-bearing mice. Tests of muscle function will include total myosin and myosin isoforms, contraction properties, and biomarkers of muscle regeneration, autophagy and myosin degradation. Findings from the proposed project will increase our understanding of the mechanisms of fatigue and depression, which will inform more effective therapies to reduce CRF and improve the functional status of cancer survivors with persistent tumor disease.