Reduced rDNA transcription diminishes skeletal muscle ribosomal capacity and protein synthesis in cancer cachexia.
Reduced rDNA transcription diminishes skeletal muscle ribosomal capacity and protein synthesis in cancer cachexia.
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癌性恶病质中rDNA转录减少降低骨骼肌核糖体能力和蛋白质合成
DOI：
10.1096/fj.202002257r
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Nader GA
中科院分区：
文献类型：
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作者：
Kim HG;Huot JR;Pin F;Guo B;Bonetto A;Nader GA
癌症中的肌肉萎缩与蛋白质合成不足有关，但这种合成代谢损伤的机制仍然知之甚少。蛋白质合成的能力主要由肌肉核糖体的丰度决定，而核糖体的丰度又受核糖体RNA基因(RDNA)的转录调控。在这项研究中，我们调查了卵巢癌临床前模型中的肌肉丢失是否与核糖体能力的降低有关，以及是否是rDNA转录受损的结果。荷瘤导致腓肠肌重量和蛋白质合成能力显著下降，并与rDNA转录和核糖体能力显著下降相一致。尽管核噬受体NUFIP1的mRNA被诱导和NUFIP1蛋白的丢失，但体外研究表明，虽然抑制自噬挽救了NUFIP1，但它并没有阻止rRNA的丢失。对体内和体外模型的rRNA片段的电泳分析表明，没有证据表明有内切核裂解，这表明rRNA的降解可能不是调节肌肉核糖体丰度的主要因素。我们的结果表明，在卵巢癌诱导的恶病质模型中，骨骼肌合成蛋白质的能力因rDNA转录减少而受损，从而降低了核糖体的能力。因此，核糖体合成受损似乎在癌症恶病质中与肌肉萎缩相关的合成代谢缺陷中起着关键作用。
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 pre-clinical 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.