Injected Nicotinamide Riboside Upregulates NAD+ in Mice, But Metabolic Effects are Minimal
Nicotinamide adenine dinucleotide (NAD) is a component of mitochondrial function in cells, and its decline with age is thought to be involved in loss of mitochondrial function. Researchers here note results from an animal study of injected nicotinamide riboside, a vitamin B3 derivative. It increased NAD+ levels, as one would expect, but does not improve measures of function related to muscle tissue. In the broader context, trials of ways to upregulate NAD+ have had mixed results, while the various vitamin B3 based approaches to increase NAD+ levels in aged tissues do not generally do as well at producing this outcome as structured exercise programs.
We designed this study to determine whether stably elevated NAD+ levels in skeletal muscle would affect insulin sensitivity or mitochondrial function in mice fed a Western diet and whether pterostilbene (PT) would interact with nicotinamide riboside (NR) on these readouts. To accomplish this, mice received daily NR injections intravenously to bypass intestinal degradation and first-pass metabolism in the liver and make NR directly available to peripheral tissues such as skeletal muscle. PT was given through the diet, owing to its insolubility in water. We successfully increased NAD+ levels not only in skeletal muscle but also inguinal white adipose tissue (iWAT). This was not simply an acute effect around the time of the injection, but rather a sustained increase throughout the intervention period. In contrast, NAD+ levels in liver were unchanged by NR at this timepoint, which could be a result of the higher NAD+ turnover in this tissue.
In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. The metabolic effects of NR and PT treatment were modest. We conclude that the chronic elevation of skeletal muscle NAD+ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimens.