Nutrition and Anabolic Interventions in Cancer Cachexia

项目总结/摘要 癌症恶病质严重消耗骨骼肌质量，导致身体功能受损， 生活质量下降。在临床领域，营养不良和恶病质是同义词。然而，恶病质 比单纯的热量缺乏更复杂，因为改善营养状况并不能逆转或防止 肌肉萎缩我们的初步数据表明，骨骼肌蛋白对合成代谢的反应， 氨基酸的刺激在癌症患者中受损。 我们认为，癌症患者骨骼肌蛋白平衡失调是由持续的 源自肿瘤和体液分解代谢因子的全身和局部骨骼肌炎症。 具体而言，这些因素通过影响合成和代谢来改变肌肉蛋白质平衡的调节。 崩溃合成受到影响，因为分解代谢因素减少了关键代谢物的血浆浓度。 支链氨基酸如亮氨酸，从而抑制营养源性厌食症的刺激。 分解是因为分解代谢因子如肿瘤坏死因子-？(TNF-?)加强核 因素-？B（NF-？B），其又通过泛素-蛋白酶体系统激活肌肉蛋白水解。我们的数据 表明，骨骼肌在癌症患者表现出增加激活NF-？B和增强型 炎症负担。最近，我们发现，3个月的睾酮治疗下调泛素 E3泛素连接酶MuRF 1和MAFbx/Atrogin-1基因表达沿着阻断A 在肌动球蛋白破坏的初始步骤中的新的14 kD肌动蛋白片段。我们的一般假设是， 补充亮氨酸增强的必需氨基酸（L-EAA）的抗厌食和抗头痛作用 伴随着睾酮的合成代谢和抗分解代谢的性质将提高瘦肌肉质量， 晚期（IIB、IIIA和IIIB期）或复发性宫颈癌患者， 蛋白质合成，并通过抑制肌肉蛋白水解的激活，分别。 我们将进行一项随机、双盲、安慰剂对照的干预研究， 机械评估新的营养（L-EAA）和药理学（睾酮）治疗，旨在 与标准护理（SOC）治疗相结合预防或使癌症相关的肌肉萎缩正常化。 我们将确定这种新的治疗方法对以下结局指标的疗效， 晚期或复发性宫颈癌患者：1）瘦体重和肌肉力量，2）肌肉 蛋白质周转和3）骨骼肌萎缩的炎性生物标志物和信号传导途径。

Project Summary/Abstract Cancer cachexia severely depletes skeletal muscle mass leading to impairments in physical function and a diminished quality of life. In the clinical realm, malnutrition and cachexia are synonymous. However, cachexia is more complex than mere caloric deficiency, since improving nutritional status does not reverse or prevent muscle wasting. Our preliminary data show that the response of skeletal muscle protein to the anabolic stimulus of amino acids is impaired in cancer patients. We propose that the dysregulation of skeletal muscle protein balance in cancer patients is altered by persistent systemic and localized skeletal muscle inflammation derived from tumoral and humoral catabolic factors. Specifically, these factors alter the regulation of muscle protein balance by affecting both synthesis and breakdown. Synthesis is affected because catabolic factors diminish the plasma concentrations of key branched-chain amino acids such as leucine, thereby suppressing the stimulus for nutrition-derived anabolism. Breakdown is affected because catabolic factors such as tumor necrosis factor-? (TNF-?) enhance nuclear factor-?B (NF-?B), which in turn activates muscle proteolysis via the ubiquitin-proteasome system. Our data demonstrate that skeletal muscle in cancer patients exhibits increased activation of NF-?B and enhanced inflammatory burden. More recently, we found that 3 months of testosterone therapy downregulates ubiquitin and the E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1 gene expression along with blocking cleavage of a novel 14-kD actin fragment in the initial step of actomyosin destruction. Our general hypothesis is that the antianorectic and anticachectic effects of leucine-enhanced essential amino acids (L-EAA) supplemented concomitantly with testosterone's anabolic and anticatabolic properties will enhance lean muscle mass in patients with advanced (stages IIB, IIIA and IIIB) or recurrent cervical carcinoma by increasing the stimulus for protein synthesis, and by inhibiting the activation of muscle proteolysis, respectively. We will conduct a randomized, double-blind, placebo-controlled intervention study designed to clinically and mechanistically assess novel nutritional (L-EAA) and pharmacologic (testosterone) therapies aimed at preventing or normalizing cancer-related muscle wasting in conjunction with standard of care (SOC) treatment. We will determine the efficacy of this novel therapeutic approach on the following outcome measures in patients with advanced or recurrent cervical carcinoma: 1) lean body mass and muscle strength, 2) muscle protein turnover, and 3) inflammatory biomarkers and signaling pathways of atrophy in skeletal muscle.