(PQB-3) Roles of skeletal muscle mass in chemotherapy-associated cachexia

描述(申请人提供)：这项研究计划的主要目标是了解化疗对肌肉质量和功能的影响，并调查肌肉肥大是否可以预防癌症恶病质，提高药物疗效和患者生存。据推测，在其他几种副作用中，化疗也是恶病质发生的原因。恶病质，即体重、肌肉和脂肪的减少，目前还没有治愈方法。导致这种综合征发生的分子机制已经研究了一段时间，但对各种癌症治疗方法对癌症恶病质的影响知之甚少。在这方面，据报道，几种抗癌药物可以引起宿主细胞的直接修饰，并导致负氮平衡。然而，调控这些过程的机制(S)值得进一步关注。我们的初步数据和其他人发表的发现支持了化疗可能会促进肌肉消耗的观点。事实上，被广泛用于治疗不同类型癌症的化疗药物，如顺铂、伊立替康和吉西他滨，在体外和体内都会导致剂量依赖的肌肉纤维损耗。同样，在携带结肠-26和HCT-116结直肠癌的小鼠身上也观察到了严重的体重减轻和肌肉萎缩。受肌肉衰竭影响的癌症患者更容易受到严重的化疗相关毒性的影响，并且与肌肉质量较大的患者不同，他们的存活率降低。其他人和我们发现，通过药物抑制肌肉抑制素家族配体来改善小鼠的肌肉质量，调节肌肉质量增长，挽救了C26-恶病质，并显著延长了生存时间。总之，这些数据表明，癌症化疗可以促进恶病质的发展，在肿瘤发生时增加肌肉质量可能会增强药物的疗效和安全性，从而延长生存期。我们的假设将通过提出以下目标来探讨：1-了解化疗对肌肉质量和功能的影响。化疗对骨骼肌的直接毒性和萎缩相关介质的间接产生将在体外和体内进行测试。转录分析将确定与化疗引起的肌肉毒性相关的基因。还将评估身体成分、肌肉功能(握力、体外收缩能力和疲劳性)、血清分析物概况(细胞因子、生长因子)和体外消耗活动。2-确定骨骼肌群的调节是否影响化疗反应和耐受性。携带大肠肿瘤(C26，HCT-116)的小鼠将接受化疗和/或ACVR2B/FC，这是一种促进肌肉生长的多肽。将分析对身体成分和肌肉功能的影响，以及血清分析物特征。还将评估肿瘤的生长和存活率。

DESCRIPTION (provided by applicant): The primary goal of this research proposal is to understand the impact of chemotherapy on muscle mass and function, and to investigate whether muscle hypertrophy can protect against cancer cachexia and improve drug efficacy and patients' survival. It has been postulated that chemotherapy, among several other side effects, is also responsible for the development of cachexia. Cachexia, i.e. loss of body weight, muscle and fat mass, has currently no cure. The molecular mechanisms responsible for the development of this syndrome have been studied for some time, however little is known about the effects of various cancer treatments on cancer cachexia. On this line, it has been reported that several anticancer drugs can cause direct host cell modification as well as induce a negative nitrogen balance. However, the mechanism(s) regulating these processes deserve further attention. Our preliminary data and others' published findings support the idea that chemotherapy might promote muscle depletion. Indeed, chemotherapeutics such as cisplatin, irinotecan and gemcitabine, widely used in the treatment of different kinds of cancer, caused dose-dependent muscle fiber wasting in vitro and in vivo. Similarly, severe body weight loss and muscle atrophy were observed in mice bearing the Colon-26 and HCT- 116 colorectal cancers. Cancer patients affected by muscle depletion were more susceptible to severe chemotherapy-associated toxicity and showed reduced survival unlike subjects with larger muscle mass. Others and we showed that improving muscle mass in mice by pharmacological inhibition of the myostatin- family ligands, regulating muscle mass growth, rescued C26-cachexia and significantly prolonged survival. Altogether, these data suggest that cancer chemotherapy can promote the development of cachexia and that increasing muscle mass in the occurrence of a tumor might enhance drugs efficacy and safety, thus also prolonging survival. Our hypothesis will be explored by proposing the following aims: 1- Understand the impact of chemotherapy on muscle mass and function. Chemotherapy-associated direct toxicity on skeletal muscle and indirect production of atrophy-associated mediators will be tested in vitro and in vivo. Transcriptomic analysis will identify genes relevant for chemotherapy-induced muscle toxicity. Body composition, muscle functions (grip strength, ex-vivo contractility and fatigability), serum analyte profiling (cytokines, growth factors) and in vitro wasting activity will also be assessed. 2- Determine whether modulation of skeletal muscle mass affects chemotherapy response and tolerability. Mice bearing colorectal tumors (C26, HCT-116) will be receiving chemotherapy and/or ACVR2B/Fc, a peptide that promotes muscle growth. Effect on body composition and muscle functionality, as well as serum analyte profiling will be analyzed. Tumor growth and survival will also be evaluated.