Llovera M, López-Soriano F J, Argilés J M
Department de Bioquímica i Fisiologia, Universitat de Barcelona, Spain.
J Natl Cancer Inst. 1993 Aug 18;85(16):1334-9. doi: 10.1093/jnci/85.16.1334.
Many cancer patients experience a wasting syndrome (cachexia) characterized by weight loss and abnormalities in carbohydrate, protein, and lipid metabolism. Recent experimental studies suggest that the development of cancer cachexia involves the host's production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha).
Our goal was to evaluate in rats the effects of an 8-day TNF-alpha treatment on overall protein metabolism in the liver, diaphragm, heart, and hind-leg muscles.
Four experimental groups corresponding to specific tissues (liver, diaphragm, heart, and hind-leg muscles) in female Wistar rats (100-150 g) were studied. Each group consisted of 25 TNF-alpha-treated and 25 control female Wistar rats. The TNF-alpha-treated rats were given intraperitoneal injections of recombinant-derived human TNF-alpha (0.5 mL) that was administered in two daily injections of 50 micrograms/kg (total dose of 100 micrograms/kg per day) for 8 days. Control animals followed the same injection schedule as the treatment group and received 0.5 mL of physiological saline instead of TNF-alpha. All rats were radioactively labeled with NaH14CO3 24 hours prior to TNF-alpha treatment. At 0, 1, 2, 4, and 8 days during TNF-alpha treatment, five rats per group were killed to measure the radioactive decay of labeled protein in specific tissues in order to estimate fractional protein turnover. During necropsy, the liver, hind-leg muscles (soleus muscle analyzed separately on 8th day only), heart, and diaphragm were rapidly weighed, and each was homogenized. Total protein content and total DNA were also determined. Total protein radioactivity and specific protein radioactivity (per milligram of protein) were evaluated for liver, diaphragm, heart, and hind-leg muscles. Radioactivity was counted in a liquid scintillation counter. Fractional rates of protein synthesis, protein degradation, total protein, and protein accumulation or loss were calculated.
The TNF-alpha treatment administered to female Wistar rats for 8 days resulted in a transient decrease in food intake and body weight 24 hours after the beginning of the TNF-alpha treatment. In all types of tissues studied, TNF-alpha treatment resulted in increases in both the protein synthesis and protein degradation, with a greater increase in the protein degradation that resulted in a reduced protein accumulation following TNF-alpha treatment. This reduction in protein accumulation was directly associated with a decreased soleus muscle mass on day 8 of the treatment.
Data suggest that TNF-alpha enhances muscle degradation in experimental situations where body weight loss is not apparent.
许多癌症患者会经历一种消瘦综合征（恶病质），其特征为体重减轻以及碳水化合物、蛋白质和脂质代谢异常。最近的实验研究表明，癌症恶病质的发展涉及宿主产生的炎性细胞因子，如肿瘤坏死因子-α（TNF-α）。
我们的目标是评估在大鼠中进行为期8天的TNF-α治疗对肝脏、膈肌、心脏和后腿肌肉中整体蛋白质代谢的影响。
对雌性Wistar大鼠（100 - 150克）中与特定组织（肝脏、膈肌、心脏和后腿肌肉）相对应的四个实验组进行了研究。每组由25只接受TNF-α治疗的雌性Wistar大鼠和25只对照雌性Wistar大鼠组成。接受TNF-α治疗的大鼠腹腔注射重组衍生的人TNF-α（0.5毫升），分两次每日注射，每次50微克/千克（每天总剂量100微克/千克），持续8天。对照动物遵循与治疗组相同的注射方案，接受0.5毫升生理盐水而非TNF-α。所有大鼠在TNF-α治疗前24小时用NaH14CO3进行放射性标记。在TNF-α治疗的第0、1、2、4和8天，每组处死5只大鼠，以测量特定组织中标记蛋白质的放射性衰变，从而估计蛋白质周转率。在尸检过程中，迅速称取肝脏、后腿肌肉（仅在第8天单独分析比目鱼肌）、心脏和膈肌的重量，并将每个组织匀浆。还测定了总蛋白含量和总DNA。评估了肝脏、膈肌、心脏和后腿肌肉的总蛋白放射性和比蛋白放射性（每毫克蛋白）。在液体闪烁计数器中计数放射性。计算蛋白质合成、蛋白质降解、总蛋白以及蛋白质积累或损失的分数率。
对雌性Wistar大鼠进行8天的TNF-α治疗导致在TNF-α治疗开始后24小时食物摄入量和体重出现短暂下降。在所有研究的组织类型中，TNF-α治疗导致蛋白质合成和蛋白质降解均增加，蛋白质降解增加幅度更大，导致TNF-α治疗后蛋白质积累减少。这种蛋白质积累的减少与治疗第8天比目鱼肌质量的下降直接相关。
数据表明，在体重减轻不明显的实验情况下，TNF-α会增强肌肉降解。
