The Role of the Central Melanocortin System in the Muscle Wasting of Cachexia

描述(由申请人提供)： 本研究的目的是了解中枢黑素皮质素系统在恶病质肌肉萎缩发病机制中的作用。患者维持瘦体重的能力是生活质量的重要因素，也是生存的重要预测因素。目前还没有治疗措施可以改善慢性病患者的瘦体重滞留。黑素皮质素系统在食欲和基础代谢率中的作用已经得到了很好的证实，但它在肌肉合成/分解代谢平衡调节中的作用还没有得到充分的研究。 黑素皮质素受体4受体(MC4R)基因敲除的小鼠瘦体重表型增加，并能抵抗恶病质中瘦体重的丧失。黑素皮质素受体的药物阻断也可以改善实验诱导的恶病质。肌肉特有的E3泛素连接酶在肌肉崩溃的发病机制中起关键作用，MAFbx和MURF-1.1已经证明，中枢黑素皮质素系统的药理激活诱导了这些基因在骨骼肌中的表达。黑素皮质素信号影响肌肉的神经解剖学途径可能是由交感神经系统通过信号介导物AMPK和FOXO转录因子家族介导的。因此，我将研究交感神经阻滞剂能否改变这一信号的传递。中枢黑素皮质素影响肌肉质量的信号通路将在药理黑素皮质素激活的背景下进行研究。然后，在存在和不存在黑素皮质素阻断的情况下，将在实验性恶病质动物模型中检验所建立的信号通路。通过比较药物激活和疾病模型，肌肉中常见的分子信号通路将被识别出来。最后，将利用逆行轨迹追踪法检查该通路的神经元连接性。将伪狂犬病病毒注射到MC4R-GFP转基因小鼠的肌肉中，并检测下丘脑MC4R阳性神经元的感染情况。 这项工作将有助于更清楚地了解恶病质中肌肉萎缩的神经成分。对这一途径的机械性理解将为这些患者的护理提供洞察力，并为合理的药物设计提供未来的靶点。

DESCRIPTION (provided by applicant): The goal of this research is to understand the role of the central melanocortin system In the pathogenesis of muscle wasting in cachexia. A patient's ability to maintain lean mass is an important factor in quality of life as well as an important predictor of survival. Currently there are no therapeutic interventions that can improve lean mass retention in chronic disease. The role of the melanocortin system in appetite and basal metabolic rate is well established, but its role in the regulation of the anabolic/catabolic balance of muscle has not been fully examined. Melanocortin 4 receptor (MC4R) knockout mice have an increased lean mass phenotype, and are resistant to loss of lean mass in cachexia. Pharmacologic blockade of melanocortin receptors also ameliorates experimentally-induced cachexia. Critical to the pathogenesis of muscle breakdown are the muscle specific E3 ubiquitin ligases, MAFbx and MuRF-1.1 have shown that pharmacological activation of the central melanocortin system induces expression of these genes in skeletal muscle. The neuroanatomical pathway by which melanocortin signaling influences muscle is likely to be mediated by the sympathetic nervous system, via the signaling mediators AMPK and the FOXO family of transcription factors. Therefore I will investigate whether the transduction of this signal can be altered by the presence of sympathetic blockade. A signaling pathway by which central melanocortins influence muscle mass will be examined in the setting of pharmacologic melanocortin activation. The signaling pathway established will then be examined in an animal model of experimental cachexia in the presence and absence of melanocortin blockade. By comparing pharmacologic activation to the disease model, a common molecular singnaling pathway in muscle will be identified. Finally, the neuronal connectivity of this pathway will be examined by utilizing a retrograde track tracing approach. Pseudorabies virus will be injected into muscle of MC4R-GFP transgenic mice, and infection of MC4R-positive neurons in the hypothalamus will be examined. This work will help develop a clearer understanding of the neural component of muscle wasting in cachexia. A mechanistic understanding of this pathway will provide insight into the care of these patients and provide future targets for rational drug design.