Increasing NAD+ Production in Muscle Alone Does Not Improve Metabolism: Preclinical Findings

Synopsis

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), precursors of NAD+, are known to help resist metabolic problems caused by high-fat diets partly by boosting oxidative metabolism in skeletal muscle. Similar benefits occur when major NAD-consuming enzymes are deleted, suggesting NAD+ availability may limit maximal muscle oxidative capacity. However, since these effects happen systemically, it's unclear whether they act directly in muscle or elsewhere. This study used a muscle-specific approach by overexpressing nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme that converts nicotinamide to NAD+, to raise NAD+ levels only in muscle (mNAMPT mice). These mice had about 50% more NAD+ in their muscles—similar to levels seen with NAD+ precursor supplements or exercise—but showed no changes in muscle mitochondrial function or resistance to high-fat diet effects. Also, increasing muscle NAD+ did not alter the NAD+/NADH balance. These results suggest that simply increasing NAD+ in muscle alone does not improve muscle metabolism or protect against high-fat diet damage, indicating that the main beneficial effects of NAD+ precursors likely come from other tissues outside of muscle and heart.

Journal

Journal of Biological Chemistry