Inflammation, muscle wasting and amino acid supplementation in the tumor-bearing state

Cachexia is common in cancer and is characterized by skeletal muscle wasting. The hypothesis of this thesis is that inflammation contributes to the loss of body weight and skeletal muscle in the tumor-bearing state through an increase in the metabolic demand for specific amino acids, specifically cysteine. Cysteine is suggested to be conditionally essential during inflammation through an increase in hepatic utilization that limits cysteine availability for peripheral tissue. To determine the role of inflammation on skeletal muscle wasting in the tumor-bearing state, the severity of inflammation was enhanced by endotoxin administration and suppressed by ibuprofen treatment. The Yoshida hepatoma increased skeletal muscle proteolysis by 38% (p=0.003) and the administration of endotoxin increased proteolysis by an additional 18% (p=0.03). The low dose of endotoxin used did not affect skeletal muscle protein metabolism in non-tumor-bearing rats; therefore it was concluded that skeletal muscle was sensitized to the catabolic effects of acute stimulation by the presence of a tumor. Ibuprofen treatment in mice bearing the colon 26 tumor reduced the loss in body weight (p=0.01) and skeletal muscle mass (p=0.02) with a partial restoration of skeletal muscle protein synthesis (p=0.03), tissue glutathione (p=0.01 for liver and p=0.04 for muscle) and plasma cyst(e)ine (p=0.03) compared to untreated tumor-bearing mice at an equal tumor burden. Dietary supplementation with cystine did not improve skeletal muscle mass or protein synthesis in colon 26-bearing mice; however, plasma and muscle cyst(e)ine concentration was also not increased with supplementation. Although cystine supplementation increased tumor cyst(e)ine concentration (p=0.009), tumor growth and protein synthesis were not affected. Cystine supplementation also reversed the positive effects of ibuprofen on body weight and skeletal muscle mass but increased the tumor response to treatment with the chemotherapeutic agent, irinotecan (p=0.01). The studies of this thesis have established the specific role of inflammation on skeletal muscle loss in the tumor-bearing state independent of the effect of inflammation on tumor progression. The data suggest that the use of non-steroidal anti-inflammatory agents may be effective in the treatment of cachexia. The exaggerated metabolic response to acute inflammatory stimulation in the tumor-bearing state suggests that infections can contribute substantially to cachexia in patients with cancer.