GLUTAMINE INTERFERES WITH GLUCOCORTICOID-INDUCED EXPRESSION Of GLUTAMINE SYNTHETASE IN SKELETAL MUSCLE 1100

Skeletal muscle atrophy from glucocorticoids is prevented by glutamine infusion. Because the gene encoding glutamine synthetase (GS) is glucocorticoid-inducible, it represented an appropriate model for testing whether glucocorticoids and glutamine exert opposing actions on the expression of specific genes related to atrophy in muscle tissue. Rats were administered hydrocortisone 21-acetate or the dosing vehicle (carboxymethyl cellulose) and were infused with saline (SAL) or glutamine (GLN, 240 mM, 0.75 ml/hr) for 7 days. Hormone treatment did not significantly lower glutamine levels in fast-twitch white or red regions of the quadriceps. Despite higher serum glutamine concentrations with amino acid infusion (1.52±0.03 (GLN) vs 1.20±0.04 (SAL) μmol/ml), muscle glutamine concentrations were not markedly increased in these fiber types. Glucocorticoid treatment produced 2-3 fold increases in plantaris, fast-twitch white, and fast-twitch red muscle GS enzyme activity and mRNA. Moreover, in all muscles/types studied, glutamine infusion diminished glucocorticoid effects on GS enzyme activity to 59-70% and on GS mRNA to 42-67% of the values in hormone-treated animals without glutamine. These data demonstrate that the therapeutic effects of glutamine in counteracting muscle atrophy are associated with a glucocorticoid-inducible gene in skeletal muscle. The absence of significant changes in muscle glutamine and the similar degree of abatement of GS expression by glutamine across all fiber types suggest a complex regulation of GS, possibly involving a systemic component.