Hickson R C, Wegrzyn L E, Osborne D F, Karl I E
School of Kinesiology, University of Illinois at Chicago 60608-1516, USA.
Am J Physiol. 1996 Nov;271(5 Pt 2):R1165-72. doi: 10.1152/ajpregu.1996.271.5.R1165.
The aims of this work were to establish whether glutamine infusion via alanyl-glutamine dipeptide provides effective therapy against muscle atrophy from glucorticoids and whether the glucocorticoid induction of glutamine synthetase (GS) is downregulated by dipeptide supplementation. Rats were given hydrocortisone 21-acetate or the dosing vehicle and were infused with alanine (AA) or alanyl-glutamine (AG) at the same concentrations and rates (1.15 mumol.min-1.100 g body wt-1, 0.75 ml/h) for 7 days. Compared with AA infusion in hormone-treated animals, AG infusion prevented total body and fast-twitch muscle mass losses by over 70%. Glucocorticoid treatment did not reduce muscle glutamine levels. Higher serum glutamine was found in the AG-infused (1.72 +/- 0.28 mumol/ml) compared with the AA-infused group (1.32 +/- 0.06 mumol/ml), but muscle glutamine concentrations were not elevated by AG infusion. Following glucocorticoid injections, GS enzyme activity was increased by two- to threefold in plantaris, fast-twitch white (superficial quadriceps), and fast-twitch red (deep quadriceps) muscle/fiber types of the AA group. Similarly, GS mRNA was elevated by 3.3- to 4.1-fold in these same muscles of hormone-treated, AA-infused rats. AG infusion diminished glucocorticoid effects on GS enzyme activity to 52-65% and on GS mRNA to 31-37% of the values with AA infusion. These results provide firsthand evidence of atrophy prevention from a catabolic state using glutamine in dipeptide form. Despite higher serum and muscle alanine levels with AA infusion than with AG infusion, alanine alone is not a sufficient stimulus to counteract muscle atrophy. The AG-induced muscle sparing is accompanied by diminished expression of a glucocorticoid-inducible gene in skeletal muscle. However, glutamine regulation of GS appears complex and may involve more regulators than muscle glutamine concentration alone.
这项工作的目的是确定通过丙氨酰谷氨酰胺二肽输注谷氨酰胺是否能有效治疗糖皮质激素引起的肌肉萎缩，以及二肽补充剂是否能下调糖皮质激素诱导的谷氨酰胺合成酶（GS）。给大鼠注射21 - 醋酸氢化可的松或给药载体，并以相同浓度和速率（1.15 μmol·min⁻¹·100 g体重⁻¹，0.75 ml/h）输注丙氨酸（AA）或丙氨酰谷氨酰胺（AG），持续7天。与激素处理动物中输注AA相比，输注AG可防止全身和快肌质量损失超过70%。糖皮质激素治疗并未降低肌肉谷氨酰胺水平。与输注AA的组（1.32 ± 0.06 μmol/ml）相比，输注AG的组血清谷氨酰胺更高（1.72 ± 0.28 μmol/ml），但输注AG并未提高肌肉谷氨酰胺浓度。注射糖皮质激素后，AA组的比目鱼肌、快缩白肌（股四头肌浅层）和快缩红肌（股四头肌深层）肌肉/纤维类型中的GS酶活性增加了两到三倍。同样，在激素处理、输注AA的大鼠的这些相同肌肉中，GS mRNA升高了3.3至4.1倍。输注AG将糖皮质激素对GS酶活性的影响降低至输注AA时值的52 - 65%，对GS mRNA的影响降低至31 - 37%。这些结果提供了使用二肽形式的谷氨酰胺预防分解代谢状态下萎缩的直接证据。尽管输注AA时血清和肌肉丙氨酸水平高于输注AG时，但单独的丙氨酸不足以抵消肌肉萎缩。AG诱导的肌肉保留伴随着骨骼肌中糖皮质激素诱导基因表达的减少。然而，谷氨酰胺对GS的调节似乎很复杂，可能涉及比单纯肌肉谷氨酰胺浓度更多的调节因子。
