Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men

Abstract

Key points This is the first long‐term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology. NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle. NR supplementation does not affect NAD metabolite concentrations in skeletal muscle. Respiration, distribution and quantity of muscle mitochondria are unaffected by NR. NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. Abstract Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) boosts NAD+ levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle‐aged, obese, insulin‐resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo‐controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12 weeks. Skeletal muscle biopsies were collected before and after the intervention. Mitochondrial respiratory capacity was determined by high‐resolution respirometry on single muscle fibres. Protein abundance and mRNA expression were measured by Western blot and quantitative PCR analyses, respectively, and in a subset of the participants (placebo n = 8; NR n = 8) we quantified mitochondrial fractional area and mitochondrial morphology by laser scanning confocal microscopy. Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD+ biosynthetic enzyme in skeletal muscle, decreased by 14% with NR. However, steady‐state NAD+ levels as well as gene expression and protein abundance of other NAD+ biosynthetic enzymes remained unchanged. Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed. Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin‐resistant men. Future studies on the effects of NR on human skeletal muscle may include both sexes and potentially provide comparisons between young and older people.

Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle

“…The low micromolar IC50 of GSK978A achieves muscle NAD elevation similar to that of natural products, such as NR (35), at less than 1% of the effective dose. The relative inability of NR to affect the MDX muscle metabolome likely stems from its poor bioavailability and short (<3 minute) half-life in the blood (8,30), which is consistent with the absence of pharmacodynamics observed in several clinical trials (36)(37)(38). However, both NADmodulating strategies employed in our study failed to improve muscle function.…”

The crosstalk of NAD, ROS and autophagy in cellular health and ageing

“…However, challenges remain in translation of laboratory findings into the design of clinical trials (Gilmour et al 2020). While some early success was found in disease outcomes of amyotrophic lateral sclerosis (ALS) (NCT03489200) (de la Rubia et al 2019), others found no benefit in patients with Alzheimer's disease (NCT00580931) (Phelan et al 2017), or studies of metabolic disorders or mitochondrial bioenergetics in men (NCT02303483) (Dollerup et al 2018(Dollerup et al , 2019a(Dollerup et al , 2019b. Although only a limited number of trials testing NAM, NMN and NR have been recently completed ([ 10) or are currently ongoing (-3), many are actively recruiting (-21) (https://clinicaltrials.gov/) (Lautrup et al 2019) and it will be interesting to see what lessons can be learned about precursor dosage, NAD ?…”

Nicotinamide, Nicotinamide Riboside and Nicotinic Acid—Emerging Roles in Replicative and Chronological Aging in Yeast

“…Published clinical data indicate that NR is safe and well-tolerated [92][93][94][95]. However, since in men with obesity no improvement has been observed following NR supplementation on some impaired physiological functions associated with obesity (glucose tolerance, mitochondrial functionality) [95][96][97], larger-scale clinical trials are required that may include women and individuals with other diseases.…”