Skeletal Muscle Atrophy and Dysfunction in Human Cancer

项目摘要 癌症及其治疗可以对骨骼肌产生深远的影响，最广为人知的是 萎缩、虚弱和氧化能力下降。这些适应及其功能性后遗症 对生活质量、治疗决策和生存率产生负面影响。尽管有这些负面影响， 促进这些骨骼肌适应的因素在人类中仍然定义不清，研究不足。 患者为了解决这一知识差距，我们在本申请中的目标是：1）检查 肌肉废用作为人类癌症患者肌肉大小和功能的调节器，2）了解如何 人肿瘤衍生因子和癌症治疗剂影响肌肉生物学并与肌肉相互作用 使用/机械刺激来调节骨骼肌的大小和功能。根据我们的初步数据， 第四，肌肉废用伴随癌症及其治疗起着不可或缺的作用的假设模型 促进肌肉萎缩和功能障碍，以响应肿瘤衍生因子和化疗药物， 人类患者和/或直接介导这些适应。因此，维持或增加肌肉 使用将减轻这些适应。提出了三个具体目标来测试这个模型：1）检查 肌肉废用对癌症患者骨骼肌大小、收缩功能和氧化能力的影响 接受治疗的患者以及通过运动维持或增加肌肉使用的效果; 2） 定义人类肿瘤衍生因子、癌症治疗对肌细胞大小和线粒体的影响， 功能及其与机械信号传导的相互作用;以及3）确定癌症及其治疗 通过肌丝蛋白氧化诱导肌肉收缩功能障碍以及是否维持或 通过锻炼增加肌肉使用可以防止这些适应。为了实现这些目标，我们将研究 非小细胞肺癌患者纵向。从骨骼肌和肿瘤获得的组织 活组织检查将用于体内和体外实验方法，沿着运动/机械 延伸干预。采用肌肉结构，功能， 代谢和信号传导，从分子到整个组织的测量，将提供数据， 实现这些目标。实现我们的目标将促进细胞和亚细胞骨骼的知识， 接受治疗的人类癌症患者的肌肉适应以及这些适应的介质。 如果成功的话，我们的研究结果可能会改变这一领域的传统思维，将废弃物作为一个重要的 人类癌症中肌肉适应的效应子。这些发现可能会影响支持性护理模式， 目前专注于癌症患者治疗后的康复，以支持活动/锻炼制度 在临床治疗连续体中更早进行干预，以更有效地减轻肌肉适应， 反过来，提高生活质量和寿命。

Project Summary Cancer and its treatment can have profound effects on skeletal muscle, the most well-recognized being atrophy, weakness and diminished oxidative capacity. These adaptations and their functional sequelae negatively impact quality of life, treatment decisions and survival. Despite these negative consequences, the factors promoting these skeletal muscle adaptations remain poorly defined and understudied in human patients. To address this gap in knowledge, our goals in this application are to: 1) to examine the role of muscle disuse as a regulator of muscle size and function in human cancer patients and 2) to understand how human tumor-derived factors and cancer therapeutics affect muscle biology and interact with muscle use/mechanical stimuli to regulate skeletal muscle size and function. Based on our preliminary data, we put forth the hypothetical model that muscle disuse accompanying cancer and its treatment plays an integral role to facilitate muscle atrophy and dysfunction in response to tumor-derived factors and chemotherapeutics in human patients and/or to mediate these adaptations directly. Accordingly, maintaining or increasing muscle use will mitigate these adaptations. Three specific aims are proposed to test this model: 1) to examine the effects of muscle disuse on skeletal muscle size, contractile function and oxidative capacity in cancer patients receiving treatment and the effects of maintaining or increasing muscle use with exercise; 2) to define the effects of human tumor-derived factors, cancer therapeutics on muscle cell size and mitochondrial function and their interaction with mechanical signaling; and 3) to determine if cancer and its treatment induce muscle contractile dysfunction through myofilament protein oxidation and whether maintaining or increasing muscle use with exercise prevents these adaptations. To accomplish these aims, we will study patients with non-small cell lung carcinoma longitudinally. Tissue acquired from skeletal muscle and tumor biopsies will be used in both in vivo and in vitro experimental approaches, along with exercise/mechanical stretch interventions. A comprehensive approach employing primary outcomes of muscle structure, function, metabolism and signaling, ranging from molecular to whole tissue measurements, will provide data to address these aims. Achieving our goals will advance knowledge of the cellular and sub-cellular skeletal muscle adaptations in human cancer patients undergoing treatment and the mediators of these adaptations. If successful, our results could shift conventional thinking in this field to include disuse as an important effector of muscle adaptations in human cancer. Such findings could influence supportive care paradigms, which currently focus on rehabilitating cancer patients after therapy, to support institution of activity/exercise interventions earlier in the clinical treatment continuum to more effectively mitigate muscle adaptations and, in turn, improve the quality and duration of life.