EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA ON SKELETAL-MUSCLE AMINO METABOLISM STUDIED IN-VIVO

Objective: The present study was performed to determine the chronology of the effects of a single 50 ug subcutaneous dose of TNF on food int ake, weight gain, and skeletal muscle protein metabolism in normal rat s. Earlier work demonstrated that a single subcutaneous dose of 50 ug of tumor necrosis factor alpha (TNF) significantly increased skeletal muscle protein synthesis and breakdown in the tumor bearing rat [1]. S ome of the earlier work demonstrated that TNF can reduce food intake, weight gain and enhance muscle catabolism. Design: Twenty-five male Sp rague Dawley rats were randomized assigned to treatment or saline arms of the study. Rates of in vivo incorporation of L-1-14C-leucine into skeletal muscle were measured by the flooding dose technique. Rats wer e studied 6 and 60 hours after TNF or saline. Results: Six hours after administration of the TNF, the total skeletal muscle amino acid conce ntration was significantly reduced by 20%. The greatest reductions wer e seen in lysine, arginine, and isoleucine (39-53%) followed by serine , tyrosine, ornithine, threonine and alanine (18-32%). Despite this dr op in skeletal muscle amino acid concentrations, the rate of skeletal muscle protein synthesis was similar to the controls (12.2 +/- 4.1 vs 13.8 +/- 3.7 %/day, mean +/- sd, saline vs TNF treated, respectively). Dietary intake (8.2 +/- 0.5 vs 7.3 +/- 1.1 g/day) and weight gain (7. 1 +/- 1.1 vs 9.1 +/- 3.8 g/day) were not affected by TNF administratio n. However, there was a significant increase in skeletal muscle protei n synthesis rate in the TNF treated group after 60 hours (17.8 +/- 4.0 vs 12.2 +/- 4.1 %/day) but not after 6 hours (13.8 +/- 3.7 vs 13.7 +/ - 3.3 %/day) compared to saline treated rats, respectively. TNF admini stration after 60 hours was not associated with an elevated skeletal m uscle 3-methyl-histidine concentration or a reduced nitrogen balance. Conclusion: These data suggest that at a 50 ug subcutaneous dose of TN F, an early (6 hours) effect is to reduce skeletal muscle of amino aci ds without effecting either synthesis or breakdown. A later effect (60 hours) is to normalize skeletal muscle amino acid concentration and t o increase skeletal muscle protein synthesis. This suggests that TNF m ay acutely alter amino acid transport as one of its modes of action.