Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance

Abstract

Nicotinamide riboside is a recently discovered form of vitamin B that can increase NAD(P) levels. NAD(P) plays key roles in energy metabolism, and its main function is the transfer of electrons in various cellular reactions. Research in aged or diseased mice reported that nicotinamide riboside increases NAD(H) levels, reduces morbidity and improves health and muscle function. We have recently shown that in healthy young rats, chronic administration of nicotinamide riboside marginally non-significantly decreased exercise performance by 35% (P = 0.071). As a follow-up to this finding, we analysed samples from these animals, in an attempt to reveal the potential mechanisms driving this adverse effect, focusing on redox homeostasis and bioenergetics. Thirty-eight Wistar rats were divided into four groups: control (n = 10), exercise (n = 9), nicotinamide riboside (n = 10) and exercise plus nicotinamide riboside (n = 9). Nicotinamide riboside was administered for 21 days [300 mg (kg body weight) daily]. At the end of administration, the exercise and the exercise plus nicotinamide riboside groups performed an incremental swimming performance test until exhaustion. Nicotinamide riboside supplementation increased the levels of NADPH in the liver (P = 0.050), increased the levels of F -isoprostanes in plasma (P = 0.047), decreased the activity of glutathione peroxidase (P = 0.017), glutathione reductase (P < 0.001) and catalase (P = 0.024) in erythrocytes, increased the level of glycogen in the liver (P < 0.001) and decreased the concentration of glucose (P = 0.016) and maximal lactate accumulation in plasma (P = 0.084). These findings support the prevailing idea that exogenously administered redox agents in heathy populations might lead to adverse effects and not necessarily to beneficial or neutral effects.

High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet

“…Since dietary NR was shown in multiple animal studies to improve metabolic health [3,5,11,12], but also was shown to either have no effect [26] or have detrimental effects depending on the dose and animal model used [19,20,21], we analyzed the long-term (18 weeks) metabolic health effects of dietary high doses of NR in HF diet-fed male C57BI/6JRccHsd mice. We compared high NR to control NR, unless indicated otherwise.…”

“…Other models with a functional Nnt gene did not show a beneficial effect of high-dose NR supplementation. For example, supplementation with 300 mg NR/kg BW/day impaired redox homeostasis in the skeletal muscle of young rats, in a model containing functional Nnt gene, leading to decreased exercise performance [20,21]. It is therefore of interest to examine the metabolic effects of high-dose NR supplementation in genetically identical mice with and without Nnt , as well as in models of impaired redox homeostasis.…”

“…Despite the demonstration of beneficial effects of NR supplementation, a limited number of studies have also indicated adverse effects of high-dose NR in rodents on either excise performance [20,21] or metabolic flexibility [19]. In view of the potential human application, the contrasting results warrant a detailed analysis of the metabolic consequences of high-dose NR supplementation on a physiological as well as a molecular level.…”

Interacting NAD+ and Cell Senescence Pathways Complicate Antiaging Therapies

“…3 One interesting exception reported a marginal decrease in exercise capacity in young rats given NR supplementation, suggesting that excess NAD + may not be helpful and even counterproductive in young healthy animals or humans. 22,23 In fact, a cottage industry has sprung around this logical narration. However, controversy has arisen over how effective the various methods to raise NAD + levels are.…”

Quantitative Redox Biology of Exercise

“…For example, the question of how much hydrogen peroxide (H 2 O 2 ) has to be increased in order to act as a signaling molecule (and not as oxidative stress) and trigger specific responses and adaptations has been a long-standing subject of discussion in exercise physiology [3]. In the same vein, how bottlenecks of redox biochemistry can be efficiently identified, such as cases in which nicotinamide adenine dinucleotide phosphate (NADPH) or reduced glutathione (GSH) become limiting, and how this information can be used to provide personalized dietary advice is still a matter of debate [4][5][6][7][8][9][10].…”