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.