NMN and NR: What Clinical Trials Reveal About Muscle Health

    Nicotinamide mononucleotide (NMN) is a compound the body uses to make NAD+, a molecule essential for energy and cellular function. In animal studies, boosting NAD+ with NMN has been shown to improve metabolism, blood sugar control, and insulin sensitivity, especially in the context of obesity and aging. These findings have led to widespread interest in NMN supplements marketed for healthy aging and metabolic support.

    NMN occurs naturally in foods like edamame, broccoli, avocado, and milk, but at very low levels—less than 2 mg per day. Supplements, in contrast, provide much higher doses, often ranging from 50 to 150 mg per capsule, with some users taking up to 300 mg daily. Despite its popularity, little was known about NMN’s effects in humans until recently.

    To address this, researchers conducted a 10-week, placebo-controlled, double-blind trial in 25 postmenopausal women who were overweight or obese and had prediabetes. Thirteen women received 250 mg of NMN daily, while twelve received placebo capsules. Before and after treatment, participants underwent detailed testing. This included scans to measure body and liver fat, a gold-standard clamp procedure to assess insulin sensitivity, muscle biopsies to examine cellular changes, and genetic analyses of muscle tissue.

    The trial showed that NMN supplementation was safe and well-tolerated, with nearly 100% adherence and no reported side effects or abnormal blood tests. However, NMN did not alter overall body fat, liver fat, fasting blood sugar, insulin, cholesterol, or hormones such as leptin and adiponectin. The most striking effect was on muscle insulin sensitivity, which improved by about 25%. This degree of improvement is comparable to the benefits typically seen after a 10% weight loss or from certain diabetes medications. No such changes were observed in the placebo group. By contrast, insulin sensitivity in the liver and fat tissue was not affected.

    At the cellular level, NMN enhanced activation of key proteins—AKT and mTOR—that are critical for insulin signaling and muscle growth. It also influenced gene activity in muscle. Compared with placebo, NMN switched on hundreds of genes linked to muscle repair and remodeling, particularly those in the PDGF signaling pathway, which helps muscles respond to insulin and regenerate. Although total NAD+ levels in muscle did not increase, NMN boosted NAD+ “turnover,” as shown by higher levels of NAD+-related metabolites. This suggests NMN may make muscles use NAD+ more dynamically.

    Despite these metabolic and molecular changes, NMN did not improve muscle strength, endurance, or mitochondrial (energy-producing) function within the 10 weeks. Its benefits appeared specific to how muscles responded to insulin, rather than to physical performance or whole-body metabolism.

    This clinical trial demonstrated that taking 250 mg of NMN daily for 10 weeks was safe and selectively improved insulin sensitivity in skeletal muscle, while also activating pathways involved in muscle remodeling and repair. While further research is needed to understand the long-term impact and whether other groups might benefit, the findings suggest NMN could play a valuable role in supporting muscle health and blood sugar control in postmenopausal women at risk of developing diabetes.

    Researchers have also tested nicotinamide riboside (NR), another NAD+ booster related to vitamin B3, to see whether similar benefits might occur. In a carefully designed crossover trial, 13 overweight or obese adults received either NR (1000 mg per day) or a placebo for six weeks, then switched to the other treatment. A wide range of tests were performed, including insulin sensitivity, energy metabolism, muscle biopsies, and advanced imaging.

    The results showed that NR increased certain markers of NAD+ activity in muscle. It also led to a small but measurable increase in lean body mass: 62.65% compared with 61.32% during placebo (an improvement of 1.34%, p = 0.02). Sleeping metabolic rate also rose with NR. In addition, levels of acetylcarnitine, a compound linked to muscle energy use, were higher in muscle tissue after NR (4558 vs. 3025 pmol/mg, an increase of 1533 pmol/mg, p = 0.04). The ability to form acetylcarnitine during exercise also improved (2.99 vs. 2.40 mmol/kg, an increase of 0.53 mmol/kg, p = 0.01). However, NR did not improve insulin sensitivity, mitochondrial function, liver or muscle fat, heart function, blood pressure, inflammation markers, or overall energy metabolism.

    An important finding from the study was that nicotinamide riboside supplements improved body composition. Specifically, participants gained more lean body mass (muscle and other fat-free tissue) and lost some fat, even though their overall weight did not change. This effect had not been reported in humans before.

    Interestingly, the benefit appeared to be stronger in women: 6 out of 7 women gained lean mass and lost fat, compared with only 1 out of 6 men. This suggests NR may affect men and women differently.

    The study also showed that NR increased people’s metabolic rate while they slept. A higher resting metabolism can help the body burn more fat. The rise in metabolism was linked to an increase in lean body mass, meaning NR’s main effect may be on supporting muscle.

    This study showed that six weeks of 1000 mg/day NR boosted NAD+ activity in muscle, slightly increased lean body mass and sleep metabolism, and improved markers of muscle energy handling.

    Comparing the two studies highlights some key differences. The NMN trial focused only on women, while the NR trial included both men and women. The NMN study showed improved muscle insulin sensitivity but no change in body composition after 10 weeks. In contrast, the NR study found no improvement in insulin sensitivity but did detect a small, significant shift in body composition over six weeks.

    The study designs also differed: the NMN trial was a parallel study comparing two separate groups, while the NR trial used a crossover design where participants served as their own controls. The supplement doses also varied. The 1000 mg of NR used in the second study is roughly equivalent to 300–400 mg of NMN. By comparison, the 250 mg dose of NMN in the first study represented about half that potential effectiveness, which may explain why body composition changes were not observed.

    Overall, these findings suggest that while both NMN and NR can influence muscle metabolism, the magnitude of their effects may vary depending on dose, study design, and participant characteristics. Future studies directly comparing equivalent doses and diverse populations will be important to clarify their relative benefits and guide practical supplementation strategies for maintaining muscle health.

References:

1.     Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021 Jun 11;372(6547):1224-1229. doi: 10.1126/science.abe9985. Epub 2021 Apr 22. PMID: 33888596; PMCID: PMC8550608.

2.     Remie CME, Roumans KHM, Moonen MPB, Connell NJ, Havekes B, Mevenkamp J, Lindeboom L, de Wit VHW, van de Weijer T, Aarts SABM, Lutgens E, Schomakers BV, Elfrink HL, Zapata-Pérez R, Houtkooper RH, Auwerx J, Hoeks J, Schrauwen-Hinderling VB, Phielix E, Schrauwen P. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr. 2020 Aug 1;112(2):413-426. doi: 10.1093/ajcn/nqaa072. PMID: 32320006; PMCID: PMC7398770.

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