Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting
Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting
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DOI：
10.1152/ajpcell.1999.276.5.c1132
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发表时间：
1999-05-01
影响因子：
5.5
通讯作者：
Price, SR
中科院分区：
文献类型：
--
作者：
Mitch, WE;Bailey, JL;Price, SR
泛素-蛋白酶体蛋白水解系统在引起肌肉萎缩的条件下受到刺激。在这些条件下启动这种反应的信号是未知的，虽然糖皮质激素是必需的，但不足以刺激肌肉蛋白水解饥饿，酸中毒和败血症。为了识别激活该系统的信号，我们研究了患有代谢性酸中毒和皮质酮产生增加的急性糖尿病大鼠。蛋白质降解增加52%（P < 0.05），编码泛素-蛋白酶体系统组分（包括泛素缀合酶E2（14 k））的mRNA水平更高（通过核径流测定，肌肉中泛素和蛋白酶体亚基C3基因的转录增加）。在糖尿病大鼠中，口服NaHCO 3预防酸血症并不能消除肌肉蛋白水解。肾上腺切除术阻断加速蛋白水解和途径mRNA的上升，这两种反应都恢复了肾上腺切除，糖尿病大鼠给予生理剂量的糖皮质激素。最后，用胰岛素治疗糖尿病大鼠大于或等于24小时逆转了肌肉蛋白水解，并将途径mRNA恢复到对照水平。因此，酸化不是这些反应所必需的，但糖皮质激素和低胰岛素水平串联激活泛素-蛋白酶体蛋白水解系统。
The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% (P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E2(14k), were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO3 did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabetic rats with insulin for greater than or equal to 24 h reversed muscle proteolysis and returned pathway mRNAs to control levels. Thus acidification is not necessary for these responses, but glucocorticoids and a low insulin level in tandem activate the ubiquitin-proteasome proteolytic system.