Glutamine synthetase expression in muscle is regulated by transcriptional and posttranscriptional mechanisms

Skeletal muscle exports glutamine (Gln) and increases the expression of the enzyme glutamine synthetase (GS) in response to physiological stress. Acut e stress or direct glucocorticoid administration raises muscle GS mRNA leve ls dramatically without a parallel increase in GS protein levels. In the lu ng, this discrepancy is caused by feedback destabilization of the GS protei n by its product Gin. It was hypothesized that muscle GS protein levels inc rease during stress only when the intracellular Gin pool has been depleted. Adult male rats were injected with the glucocorticoid hormone dexamethason e (DEX) to mimic the acute stress response and with the GS inhibitor methio nine sulfoximine (MSO) to deplete muscle Gin stores. DEX increased GS mRNA levels by 2.8-fold but increased GS protein levels by an average of only 40 %. MSO diminished muscle GLN levels by 68% and caused GS protein levels to rise in accordance with GS mRNA. Chronic stress was mimicked using 6 days o f MSO treatment, which produced anorexia, 23% loss of body weight, and 64% decrease in muscle Gin levels, as well as pronounced in creases in both mus cle GS mRNA(26-fold) and protein levels (35-fold) without elevation of plas ma glucocorticoid levels. Calorie-restricted pair-fed animals exhibited les ser increases in muscle GS mRNA (8-fold) and protein levels (5-fold) withou t a decline in muscle Gin content. Thus regulation of GS expression in both acute and chronic stress involved both transcriptional and posttranscripti onal mechanisms, perhaps affected by muscle Gin content.