PO.TB01.01 · 肿瘤生物学
Apelin是神经肌肉接头从癌症恶病质中恢复的候选驱动因子
Apelin is a candidate driver for neuromuscular junction recovery from cancer cachexia
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症恶病质是一种影响多个器官的全身性消耗性疾病,无法从该状态恢复最终导致死亡。据估计其影响多达80%的癌症患者,并占癌症死亡的高达20%。癌症恶病质以负能量平衡为特征,导致体重减轻和器官萎缩。癌症恶病质导致身体能力下降、治疗疗效降低,以及死亡率和发病率升高。有新兴证据表明,激素信号驱动癌症恶病质发展中的器官间变化,包括大脑、肝脏和肌肉的变化。我开发了一种癌症恶病质小鼠模型,可在同一动物中研究癌症恶病质的发展和恢复。使用该模型,我观察到癌症恶病质发展期间肌肉量减少,以及癌症恶病质恢复期间肌肉量增加。通过对恶病质和恢复期小鼠的股四头肌RNA测序数据进行无偏分析,我识别出一簇指示神经肌肉接头改变的基因。这提示神经肌肉接头(NMJ)可能在癌症恶病质的肌肉萎缩和再生中发挥作用。通过将分析聚焦于循环激素,我识别出apelin是癌症恶病质恢复期间骨骼肌中上调最显著的激素。Apelin已与年龄相关的肌肉萎缩、肌肉功能和神经肌肉接头相关联。我在全身水平调节了apelin水平,并证明全身性给予apelin可降低肌肉内E3连接酶(蛋白降解)并增加小腿肌肉中的Pax7(再生)标志物。这些发现已通过详细的组织病理学分析得到证实。我的工作建立了一个新颖的小鼠模型,能够在同一批小鼠中研究恶病质的发展和恢复。该模型可能带来能预防或治疗癌症恶病质的新治疗选择的发现。此外,我的工作提示可能存在用于加速肌肉从癌症恶病质中恢复的潜在可靶向机制。
查看英文原文 English abstract
Cancer cachexia is a systemic wasting condition that affects multiple organs and failure to recover from the condition ultimately leads to death. It is estimated to affect as many as 80% of patients with cancer and accounts for up to 20% of cancer deaths. Cancer cachexia is characterized by negative energy balance leading to weight loss and organ atrophy. Cancer cachexia results in decreased physical ability, reduced therapy efficacy, and increased mortality and morbidity. There is emerging evidence that hormone signaling drives inter-organ changes in cancer cachexia development, including changes in the brain, liver and muscle. I have developed a cancer cachexia mouse model in which both cancer cachexia development and recovery can be studied in the same animal. Using this model, I observed decreased muscle mass during cancer cachexia development and increased muscle mass during cancer cachexia recovery. By performing unbiased analyses on quadriceps RNA sequencing data from cachectic and recovering mouse, I identified a cluster of genes indicating alterations in the neuromuscular junctions. This suggests that neuromuscular junctions (NMJ) may play a role in muscle atrophy and regeneration in cancer cachexia. By focusing my analyses on circulating hormones, I identified apelin as the most upregulated hormone in the skeletal muscle during cancer cachexia recovery. Apelin has been associated with age-related muscle atrophy, muscle function and the neuromuscular junction. I have modulated apelin level systemically and demonstrated that systemic apelin administration decreased intramuscular E3 ligase (protein degradation) and increased Pax7 (regeneration) marker in the lower leg muscle. These findings have been corroborated by detailed histopathology analyses. My work establishes a novel mouse model that enables studying cachexia development and recovery in the same mice. This model may lead to the discovery of new treatment options that can prevent or treat cancer cachexia. In addition, my work suggests that there may be potential targetable mechanisms for accelerating muscle recovery from cancer cachexia.
利益披露 Disclosure
A. Wang, None.