Department of Kinesiology, The Pennsylvania State University, University Park, PA, USA.
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
FASEB J. 2021 Feb;35(2):e21335. doi: 10.1096/fj.202002257R.
Muscle wasting in cancer is associated with deficits in protein synthesis, yet, the mechanisms underlying this anabolic impairment remain poorly understood. The capacity for protein synthesis is mainly determined by the abundance of muscle ribosomes, which is in turn regulated by transcription of the ribosomal (r)RNA genes (rDNA). In this study, we investigated whether muscle loss in a preclinical model of ovarian cancer is associated with a reduction in ribosomal capacity and was a consequence of impaired rDNA transcription. Tumor bearing resulted in a significant loss in gastrocnemius muscle weight and protein synthesis capacity, and was consistent with a significant reduction in rDNA transcription and ribosomal capacity. Despite the induction of the ribophagy receptor NUFIP1 mRNA and the loss of NUFIP1 protein, in vitro studies revealed that while inhibition of autophagy rescued NUFIP1, it did not prevent the loss of rRNA. Electrophoretic analysis of rRNA fragmentation from both in vivo and in vitro models showed no evidence of endonucleolytic cleavage, suggesting that rRNA degradation may not play a major role in modulating muscle ribosome abundance. Our results indicate that in this model of ovarian cancer-induced cachexia, the ability of skeletal muscle to synthesize protein is compromised by a reduction in rDNA transcription and consequently a lower ribosomal capacity. Thus, impaired ribosomal production appears to play a key role in the anabolic deficits associated with muscle wasting in cancer cachexia.
癌症导致的肌肉消耗与蛋白质合成不足有关，但这种合成代谢受损的机制仍知之甚少。蛋白质合成的能力主要取决于肌肉核糖体的丰度，而核糖体（r）RNA 基因（rDNA）的转录又调节着核糖体的丰度。在这项研究中，我们研究了卵巢癌临床前模型中的肌肉损失是否与核糖体容量的减少有关，以及是否是由于 rDNA 转录受损所致。肿瘤的生长导致比目鱼肌重量和蛋白质合成能力显著下降，这与 rDNA 转录和核糖体容量的显著减少一致。尽管诱导了核糖体自噬受体 NUFIP1mRNA 的产生并导致 NUFIP1 蛋白的丢失，但体外研究表明，尽管自噬抑制可以挽救 NUFIP1，但不能防止 rRNA 的丢失。来自体内和体外模型的 rRNA 片段电泳分析没有证据表明存在内切核酸酶切割，这表明 rRNA 降解可能不是调节骨骼肌核糖体丰度的主要因素。我们的研究结果表明，在这种卵巢癌诱导恶病质的模型中，骨骼肌合成蛋白质的能力因 rDNA 转录减少和核糖体容量降低而受损。因此，核糖体产生受损似乎在与癌症恶病质相关的肌肉消耗的合成代谢缺陷中起着关键作用。
