EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA ON MUSCLE-PROTEIN TURNOVER IN FEMALE WISTAR RATS

Background: Many cancer patients experience a wasting syndrome (cachex ia) characterized by weight loss and abnormalities in carbohydrate, pr otein, and lipid metabolism. Recent experimental studies suggest that the development of cancer cachexia involves the host's production of i nflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). Purpose: 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. Methods: Four experimental groups corre sponding to specific tissues (liver, diaphragm, heart, and hind-leg mu scles) in female Wistar rats (100-150 g) were studied. Each group cons isted of 25 TNF-alpha-treated and 25 control female Wistar rats. The T NF-alpha-treated rats were given intraperitoneal injections of recombi nant-derived human TNF-alpha (0.5 mL) that was administered in two dai ly injections of 50 mug/kg (total dose of 100 mug/kg per day) for 8 da ys. Control animals followed the same injection schedule as the treatm ent group and received 0.5 mL of physiological saline instead of TNF-a lpha. All rats were radioactively labeled with (NaHCO3)-C-14 24 hours prior to TNF-alpha treatment. At 0, 1, 2, 4, and 8 days during TNF-alp ha treatment, five rats per group were killed to measure the radioacti ve decay of labeled protein in specific tissues in order to estimate f ractional protein turnover. During necropsy, the liver, hind-leg muscl es (soleus muscle analyzed separately on 8th day only), heart, and dia phragm were rapidly weighed, and each was homogenized. Total protein c ontent and total DNA were also determined. Total protein radioactivity and specific protein radioactivity (per milligram of protein) were ev aluated for liver, diaphragm, heart, and hind-leg muscles. Radioactivi ty was counted in a liquid scintillation counter. Fractional rates of protein synthesis, protein degradation, total protein, and protein acc umulation or loss were calculated. Results: The TNF-alpha treatment ad ministered to female Wistar rats for 8 days resulted in a transient de crease in food intake and body weight 24 hours after the beginning of the TNF-alpha treatment. In all types of tissues studied, TNF-alpha tr eatment resulted in increases in both the protein synthesis and protei n degradation, with a greater increase in the protein degradation that resulted in a reduced protein accumulation following TNF-alpha treatm ent. This reduction in protein accumulation was directly associated wi th a decreased soleus muscle mass on day 8 of the treatment. Conclusio ns: Data suggest that TNF-alpha enhances muscle degradation in experim ental situations where body weight loss is not apparent.