Experimental Medicine and Clinical Pathology Unit, Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Nat Commun. 2023 Apr 3;14(1):1849. doi: 10.1038/s41467-023-37595-6.
Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD and downregulation of Nrk2, an NAD biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD repletion therapy in cachectic mice reveals that NAD precursor, vitamin B3 niacin, efficiently corrects tissue NAD levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD in the pathophysiology of human cancer cachexia. Overall, our results propose NAD metabolism as a therapy target for cachectic cancer patients.
恶病质是一种消耗性的衰弱综合征，在癌症患者中非常普遍。它表现为能量和线粒体代谢异常，导致组织消耗。我们最近发现烟酰胺腺嘌呤二核苷酸（NAD）的损失与癌症宿主的肌肉线粒体功能障碍有关。在这项研究中，我们证实了 NAD 的耗竭和 NAD 生物合成酶 Nrk2 的下调是不同小鼠模型中严重恶病质的共同特征。在恶病质小鼠中测试 NAD 补充治疗表明，NAD 前体烟酰胺（维生素 B3）可有效纠正组织 NAD 水平，改善线粒体代谢，并改善癌症和化疗引起的恶病质。在临床环境中，我们发现肌肉 NRK2 在癌症患者中下调。NRK2 的低表达与代谢异常相关，这突显了 NAD 在人类癌症恶病质病理生理学中的重要性。总的来说，我们的结果提出 NAD 代谢作为恶病质癌症患者的治疗靶点。
