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

描述(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性疲劳(CRF)，通常伴随着抑郁的情绪和肌肉无力。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的升高有关。这些细胞因子具有多个靶器官效应，与了解CRF的症状有关。在肌肉中，它们抑制肌肉发生，导致自噬和肌球蛋白的降解，导致肌肉质量损失和收缩力量减弱。在大脑中，细胞因子增加了一种酶的表达，这种酶减少了5-羟色胺的合成，5-羟色胺是一种参与调节情绪和运动活动的神经递质，并增加了其他具有神经抑制作用的色氨酸代谢物的合成，与抑郁的情绪有关。本项目的目的是在慢性肾功能衰竭动物模型中了解细胞因子在导致抑郁情绪和骨骼肌萎缩的分子通路上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、肌肉萎缩的生物标志物和抑郁之间的因果关系，其中疲劳被建模为自愿车轮跑步活动(VWRA)减少，抑郁情绪被建模为快感丧失，即对糖水的减少偏好。荷瘤小鼠将接受米诺环素治疗，以减少细胞因子的表达；布洛芬，以减少TNFa诱导的骨骼肌损耗的下游介质的活性；氟西汀，一种选择性的5-羟色胺再摄取抑制剂(SSRI)，或1-甲基色氨酸，一种色氨酸代谢的竞争性拮抗剂。目的2是确定在自由奔跑和久坐不动的荷瘤小鼠中，缺乏运动是否夸大了肿瘤生长对肌肉功能和情绪的影响。肌肉功能测试将包括总肌球蛋白和肌球蛋白亚型、收缩特性以及肌肉再生、自噬和肌球蛋白降解的生物标志物。拟议项目的发现将增加我们对疲劳和抑郁机制的理解，这将为减少CRF和改善患有持续性肿瘤疾病的癌症幸存者的功能状态提供更有效的治疗方案。

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.