A bstract 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.
Cancer cachexia (CC) is a syndrome in cancer patients characterized by muscle wasting and weight loss, impacting their quality of life and survival. Mitochondrial dysfunction and NAD+ depletion are significant features of CC. NAD+ is essential for mitochondrial functions and muscle health.
Studies in mice with cancer have shown that mitochondrial oxidative phosphorylation (OXPHOS) declines with NAD+ depletion in muscle. The enzyme nicotinamide riboside kinase 2 (Nrk2), important for NAD+ biosynthesis, is downregulated in CC, affecting NAD+ levels. Supplementation with niacin (NA) can improve NAD+ levels and muscle function.
This study aims to understand NAD+ metabolism impairments in CC and test NA’s therapeutic potential. Results show that NAD+ deficiency and Nrk2 downregulation are common in CC. NA supplementation corrected NAD+ deficiency, boosted mitochondrial biogenesis, and partially restored muscle mass and energy metabolism in cachectic mice. Thus, targeting NAD+ metabolism could help manage cancer cachexia.
