NAD+ repletion with niacin counteracts cancer cachexia

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.

Abstracts

“…Hepatic metabolism alterations and effects of niacin supplementation in experimental cancerand chemotherapy-induced cachexia Introduction: Alterations in hepatic function influence energy expenditure in cancer patients and could play an important role in the development and progression of cancer cachexia, a progressive metabolic syndrome that results in depletion of skeletal muscle [1,2]. In cachectic mice, niacin (NA) supplementation ameliorated cancer-and chemotherapy-induced cachexia while repleting hepatic NAD metabolite levels, suggesting that a relevant part of the NA effects may be mediated by the improvement of liver metabolism [3]. Therefore, the objective of this project was to evaluate the differences in the liver metabolism of healthy mice and cancer/chemotherapy cachectic mice with or without niacin supplementation.…”

“…Introduction: Low skeletal muscle index (SMI) is an established prognostic indicator in cancer 1 , and may also be associated with poor health-related quality of life (HRQOL) 2 . Presence or risk of malnutrition is also associated with poor survival and HRQOL outcomes 3,4 , yet this confounding factor is rarely accounted for in studies investigating the consequences of low SMI. Malnutrition is prevalent in upper gastrointestinal (GI) cancer 5 , therefore this study examined the effect of malnutrition risk on the association between SMI at diagnosis of upper GI cancer, and both HRQOL at diagnosis and survival over the following year.…”

“…Novel biomarkers as possible prognostic tools in the determination of muscle wasting in HF patients Tania Garfias-Veitl 1,2 * , Sascha Dierks 1 , Mirela Vatic 1,2 , Ryosuke Sato 1 , Guglielmo Fibbi 1 , Wolfram Doehner 3,4,5 , Stefan D. Anker 3,5,6 & Stephan von Haehling 1,2 1 Background: Muscle wasting is a co-morbidity gaining attention among heart failure (HF) patients and older adults. According to the European Society of Cardiology, its prevalence in HF ranges from 20 to 50%.…”

“…Higher fibroblast growth factor 23 levels are associated with low exercise capacity in patients with chronic heart failure: results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) Ryosuke Sato 1 * , Tania Garfias-Veitl , Mirela Vatic 1,2 , Guglielmo Fibbi 1 , Wolfram Doehner 3,4,5 Stefan D. Anker 3,5,6 & Stephan von Haehling Introduction: Fibroblast growth factor 23 (FGF-23) is a key regulator of phosphate metabolism, inhibiting phosphate reabsorption and vitamin D activation in the proximal renal tubules. Meanwhile, several studies have shown that higher FGF-23 levels are associated with disease severity and adverse outcomes in heart failure (HF).…”

“…Association between sarcopenia and urinary dysfunction in patients with dysphagia Hidetaka Wakabayashi 1 * , Shingo Kakehi 1 , Shinta Nishioka 2 & Ryo Momosaki 3 1 Department of Rehabilitation Medicine, Tokyo Women's Medical University Hospital, Tokyo, Japan, 2 Department of Clinical Nutrition and Food Service, Nagasaki Rehabilitation Hospital, Nagasaki, Japan, 3…”