NAD+ repletion with niacin counteracts cancer cachexia

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. The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia.

Automated summary

NAD(+) loss is associated with muscle mitochondrial dysfunction in cancer hosts. Niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia. Downregulation of muscle NRK2 is correlated with metabolic abnormalities in cancer patients, highlighting the significance of NAD(+) in the pathophysiology of human cancer cachexia.