Medina R, Wing S S, Haas A, Goldberg A L
Department of Cellular and Molecular Physiology, Harvard Medical School, Boston, MA 02115.
Biomed Biochim Acta. 1991;50(4-6):347-56.
The rapid atrophy of skeletal muscles upon fasting or denervation is due largely to an increased rate of protein breakdown. Blocking the lysosomal or the Ca(2+)-dependent pathways did not prevent increased proteolysis in muscles from fasted animals or following denervation. In contrast, upon food deprivation, the nonlysosomal ATP-dependent process increased by 150-350%. After refeeding, this process returned to control levels by 24 h. Similarly, within one day after denervation of the soleus, proteolysis increased by 50-250%. By contrast, the residual energy-independent process did not change in fasting or denervation. Because the ATP-dependent process might involve activation of the ubiquitin-ATP-dependent pathway, we measured the levels of mRNA for ubiquitin [Ub] in the atrophying muscles. After food deprivation, the levels of polyUb transcripts increased 2- to 4-fold in the soleus and extensor digitorum longus (EDL) muscles, and returned to control levels within 1 day of refeeding. After denervation of the soleus, a 2- to 3-fold increase in polyUb mRNA also occurred within 1 day. The muscle content of ubiquitinated protein also changed in parallel with Ub mRNA levels under these conditions. Thus, polyUb genes appear to be selectively induced in atrophying muscle, and levels of Ub mRNA and ubiquitin-protein conjugates change coordinately with the rate of ATP-dependent proteolysis. These data suggest that in atrophying muscle the ATP-Ub-dependent system plays an important physiological role in the degradation of the bulk of cell proteins.
禁食或去神经支配后骨骼肌的快速萎缩主要是由于蛋白质分解速率增加所致。阻断溶酶体或钙依赖性途径并不能阻止禁食动物肌肉或去神经支配后蛋白质水解的增加。相反，在食物缺乏时，非溶酶体ATP依赖性过程增加了150% - 350%。重新喂食后，该过程在24小时内恢复到对照水平。同样，比目鱼肌去神经支配一天内，蛋白质水解增加了50% - 250%。相比之下，残余的不依赖能量的过程在禁食或去神经支配时没有变化。由于ATP依赖性过程可能涉及泛素 - ATP依赖性途径的激活，我们测量了萎缩肌肉中泛素[Ub]的mRNA水平。食物缺乏后，比目鱼肌和趾长伸肌（EDL）中多聚泛素转录本水平增加了2至4倍，并在重新喂食1天内恢复到对照水平。比目鱼肌去神经支配后1天内，多聚泛素mRNA也增加了2至3倍。在这些条件下，泛素化蛋白的肌肉含量也与泛素mRNA水平平行变化。因此，多聚泛素基因似乎在萎缩肌肉中被选择性诱导，泛素mRNA水平和泛素 - 蛋白缀合物与ATP依赖性蛋白水解速率协调变化。这些数据表明，在萎缩肌肉中，ATP - 泛素依赖性系统在大部分细胞蛋白的降解中起重要生理作用。
