NAD+ repletion with niacin counteracts cancer cachexia

Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y. Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E. Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J. Hulmi, Roberta Sartori (), Eija Pirinen () and Fabio Penna ()
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Marc Beltrà: University of Torino
Noora Pöllänen: University of Helsinki
Claudia Fornelli: University of Torino
Kialiina Tonttila: University of Helsinki
Myriam Y. Hsu: University of Torino
Sandra Zampieri: University of Padova
Lucia Moletta: University of Padova
Samantha Corrà: Veneto Institute of Molecular Medicine
Paolo E. Porporato: University of Torino
Riikka Kivelä: University of Helsinki
Carlo Viscomi: University of Padova
Marco Sandri: University of Padova
Juha J. Hulmi: University of Jyväskylä
Roberta Sartori: University of Padova
Eija Pirinen: University of Helsinki
Fabio Penna: University of Torino

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37595-6

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