Calorie restriction without malnutrition (CR) is considered as the most effective nongenetic nor pharmacological intervention that promotes healthy aging phenotypes and can extend lifespan in most model organisms. Lifelong CR leads to an increase of cytochrome b₅ reductase-3 (CYB5R3) expression and activity. Overexpression of CYB5R3 confers some of the salutary effects of CR, although the mechanisms involved might be independent because key aspects of energy metabolism and lipid profiles of tissues go in opposite ways. It is thus important to study if some of the metabolic adaptations induced by CR are affected by CYB5R3 overexpression. CYB5R3 overexpression greatly preserved body and liver weight in mice under CR conditions. In liver, CR did not modify mitochondrial abundance, but lead to increased expression of mitofusin Mfn2 and TFAM, a transcription factor involved in mitochondrial biogenesis. These changes were prevented by CYB5R3 overexpression but resulted in a decreased expression of a different mitochondrial biogenesis-related transcription factor, Nrf1. In skeletal muscle, CR strongly increased mitochondrial mass, mitofusin Mfn1, and Nrf1. However, CYB5R3 mice on CR did not show increase in muscle mitochondrial mass, regardless of a clear increase in expression of TFAM and mitochondrial complexes in this tissue. Our results support that CYB5R3 overexpression significantly modifies the metabolic adaptations of mice to CR.

中文翻译：

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肝脏和骨骼肌中线粒体对长寿营养和遗传干预的适应性：转基因小鼠卡路里限制与 CYB5R3 过表达之间的串扰。

没有营养不良的热量限制 (CR) 被认为是最有效的非遗传或药物干预措施，可促进健康的衰老表型，并可以延长大多数模式生物的寿命。终身 CR 导致细胞色素b _5增加还原酶 3 (CYB5R3) 的表达和活性。CYB5R3 的过度表达赋予了 CR 的一些有益效果，尽管所涉及的机制可能是独立的，因为能量代谢的关键方面和组织的脂质分布是相反的。因此，重要的是研究 CR 诱导的某些代谢适应是否受到 CYB5R3 过表达的影响。在 CR 条件下，CYB5R3 过表达极大地保留了小鼠的体重和肝脏重量。在肝脏中，CR 没有改变线粒体丰度，但导致线粒体融合素 Mfn2 和 TFAM 的表达增加，TFAM 是一种参与线粒体生物发生的转录因子。CYB5R3 过表达阻止了这些变化，但导致不同线粒体生物发生相关转录因子 Nrf1 的表达降低。在骨骼肌中，CR 强烈增加线粒体质量、mitofusin Mfn1 和 Nrf1。然而，CR 上的 CYB5R3 小鼠没有表现出肌肉线粒体质量的增加，尽管该组织中 TFAM 和线粒体复合物的表达明显增加。我们的结果支持 CYB5R3 过表达显着改变了小鼠对 CR 的代谢适应。