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.