METABOLIC-ACIDOSIS STIMULATES MUSCLE PROTEIN-DEGRADATION BY ACTIVATING THE ADENOSINE TRIPHOSPHATE-DEPENDENT PATHWAY INVOLVING UBIQUITIN AND PROTEASOMES
METABOLIC-ACIDOSIS STIMULATES MUSCLE PROTEIN-DEGRADATION BY ACTIVATING THE ADENOSINE TRIPHOSPHATE-DEPENDENT PATHWAY INVOLVING UBIQUITIN AND PROTEASOMES
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DOI：
10.1172/jci117208
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发表时间：
1994-05-01
影响因子：
15.9
通讯作者：
GOLDBERG, AL
中科院分区：
文献类型：
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作者：
MITCH, WE;MEDINA, R;GOLDBERG, AL
代谢性酸中毒通常导致身体蛋白质的损失，主要是由于肌肉中蛋白质的加速分解。为了确定哪种蛋白水解途径被激活，我们测量了在阻断不同蛋白水解系统的条件下，酸中毒（NH 4Cl处理）和成对喂养大鼠的孵育的上滑车肌中的蛋白质降解。抑制溶酶体和钙激活蛋白酶并没有减少酸中毒诱导的肌肉蛋白水解增加。然而，当ATP的产生也被阻止，蛋白水解下降到相同的低水平，在酸中毒和对照组大鼠的肌肉。因此，酸中毒选择性地刺激ATP依赖的非溶酶体的蛋白水解过程，我们还研究了激活的途径是否涉及泛素和蛋白酶体（多催化蛋白酶）。酸中毒与肌肉中泛素mRNA增加2.5至4倍有关。肌肉热休克蛋白70 mRNA或肾脏泛素mRNA没有增加，表明反应的特异性。肌肉中的泛素mRNA在酸中毒停止后24小时内恢复到对照水平。肌肉中蛋白酶体（C2和C3）亚基的mRNA也分别增加了4倍和2.5倍，酸中毒;组织蛋白酶B的mRNA没有变化。这些结果与酸中毒通过激活ATP-泛素-蛋白酶体依赖性蛋白水解途径刺激肌肉蛋白水解一致，但不能证明这一点。
Metabolic acidosis often leads to loss of body protein due mainly to accelerated protein breakdown in muscle. To identify which proteolytic pathway is activated, we measured protein degradation in incubated epitrochlearis muscles from acidotic (NH4Cl-treated) and pair-fed rats under conditions that block different proteolytic systems. Inhibiting lysosomal and calcium-activated proteases did not reduce the acidosis-induced increase in muscle proteolysis. However, when ATP production was also blocked, proteolysis fell to the same low level in muscles of acidotic and control rats. Acidosis, therefore, stimulates selectively an ATP-dependent, nonlysosomal, proteolytic process.We also examined whether the activated pathway involves ubiquitin and proteasomes( multicatalytic proteinases). Acidosis was associated with a 2.5- to 4-fold increase in ubiquitin mRNA in muscle. There was no increase in muscle heat shock protein 70 mRNA or in kidney ubiquitin mRNA, suggesting specificity of the response. Ubiquitin mRNA in muscle returned to control levels within 24 h after cessation of acidosis. mRNA for subunits of the proteasome (C2 and C3) in muscle were also increased 4-fold and 2.5-fold, respectively, with acidosis; mRNA for cathepsin B did not change. These results are consistent with, but do not prove that acidosis stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent, proteolytic pathway.