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

描述（由申请人提供）：本研究提案的主要目标是了解化疗对肌肉质量和功能的影响，并研究肌肉肥大是否可以预防癌症恶病质并提高药物疗效和患者生存率。 据推测，化疗，在其他几个副作用，也是恶病质的发展负责。恶病质，即体重、肌肉和脂肪量的损失，目前没有治愈方法。负责这种综合征的发展的分子机制已经研究了一段时间，但是关于各种癌症治疗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直接的宿主细胞修饰以及诱导负氮平衡。然而，这些进程的调控机制值得进一步关注。 我们的初步数据和其他人发表的发现支持化疗可能促进肌肉消耗的观点。事实上，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引起剂量依赖性肌纤维消耗。类似地，在携带Colon-26和HCT- 116结肠直肠癌的小鼠中观察到严重的体重减轻和肌肉萎缩。受肌肉耗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受试者不同，生存率降低。其他人和我们表明，通过药理学抑制肌生长抑制素家族配体来改善小鼠的肌肉质量，调节肌肉质量生长，挽救了C26-恶病质并显著延长了生存期。总之，这些数据表明，癌症化疗可以促进恶病质的发展，并且在肿瘤发生时增加肌肉质量可能会提高药物的有效性和安全性，从而延长生存期。我们的假设将通过提出以下目标进行探索：1-了解化疗对肌肉质量和功能的影响。将在体外和体内检测化疗相关的骨骼肌直接毒性和萎缩相关介质的间接产生。转录组学分析将鉴定与化疗诱导的肌肉毒性相关的基因。还将评估身体组成、肌肉功能（握力、离体收缩性和疲劳性）、血清分析物分析（细胞因子、生长因子）和体外消耗活性。2-确定骨骼肌质量的调节是否影响化疗反应和耐受性。携带结肠直肠肿瘤的小鼠（C26，HCT-116）将接受化疗和/或ACVR 2B/Fc，一种促进肌肉生长的肽。将分析对身体成分和肌肉功能的影响以及血清分析物分析。还将评价肿瘤生长和存活。

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.