## 2 Effects of Nicotinamide Riboside on Several Organs and Systems
### Nicotinamide Riboside and the Musculoskeletal System  
Numerous preclinical studies have suggested that NR and NMN dietary supplements increase NAD\({}^{+}\) levels in the skeletal muscle and help protect musculoskeletal system from age-related metabolic dysfunction. NAD\({}^{+}\) biosynthesis pathways/homeostasis and its bioavailability in skeletal muscle cells are influenced by NAM phosphoribosyltransferaseterase (NAMPT), NRK1, and NRK2 enzymes [118; 119]. After the application of NRS in hexose-6-phosphate dehydrogenase KO (H6 PDKO) mice, NAD\({}^{+}\)/NADH ratio was elevated but without any effect on insulin sensitivity, MT respiratory dysfunctions (MT acylcarnitine), acetyl coenzyme A metabolism and endoplasmic reticulum OXS [120; 121]. In a double-blind, PLA-controlled, randomized, crossover trial for 21 days, 12 aged men were supplemented with 1 g/day NR. It was found that both MT bioenergetics and skeletal muscle NAD\({}^{+}\) metabolism were stimulated by NRS; at the same time, the amounts of serum inflammatory cytokines were reduced [122]. Moreover, in a randomized, double-blinded, PLA-controlled, crossover intervention study in 13 healthy obese humans, NRS (1 g daily for six weeks) induced some minor modifications in body composition and sleeping metabolic rate, increased the level of NAD\({}^{+}\) metabolites, such as NA adenine dinucleotide and MeNAM, and altered the acylcarnitine concentrations in the skeletal muscle [123]. Recent studies showed that, in healthy humans, oral NAD\({}^{+}\) supplementation (NR, NMN) does not alter whole-body or skeletal muscle metabolic responses to an endurance exercise [124; 125]. During endurance exercises, one week of NRS (1 g daily) for eight young males did influence neither skeletal muscle MT respiration nor auto-PARylation of poly ADP-ribose polymerase 1 (PARP1), acetylation of tumor protein 53 (p53) Lys382 and MnSODLys122, or overall acetylation [126]. A recent randomized controlled trial testing of in-home aerobic and exercise training and 16 weeks NRS targeted the skeletal muscle MT OXPHOS and improved the muscle mass and fitness in adolescent and young adult survivors of hematopoietic cell transplantation (HemSCT) [127]. However, some preclinical studies showed that, compared to the CON group, chronic NRS (300 mg/kg/day for 21 days by oral gavage) decreases the exercise/swimming performance in Wistar rats. The redox features and pleiotropic metabolism of NAD\({}^{+}\) and NADP\({}^{+}\) could be an explanation for the potential inhibition of oral NR treatment on physical performance of rats [128; 129; 130]. NAD\({}^{+}\) repletion improves MT activity and muscle stem cells (MuSCs) function and enhances life span in aged mice. In an experimental model of muscular dystrophy, NRS prevented the senescence of MuSC in the mdx (C57 BL/10 ScSn-Dmd(mdx)/J) mice [131; 132]. Also, seeking treatment of MT myopathy, orally administered NR was found to induce MT unfolded protein response, MT biogenesis in brown adipose tissue (BAT) and skeletal muscle, prevent abnormalities of MT ultrastructure, and prevent deletion of mtDNA [133]. In this regard, NRS increased the levels of NAD\({}^{+}\) in liver and skeletal muscle, exercise capacity, and MT respiration, alleviating the exercise intolerance in adenine nucleotide translocator 1 (ANT1)-deficient mice [134]. In the recent study on 20 body mass index (BMI)-discordant monozygotic twin pairs, NRS (250 mg to 1 g daily for five months) improved muscle MT biogenesis, satellite cell differentiation, and gut microbiota [135]. NAD\({}^{+}\) boosting was prelimically characterized as a promising therapeutic approach for rheumatoid arthritis (RA) patients. NR and NMN treatments were ex vivo tested on RA-PBMCs, thus highlighting NAD\({}^{+}\) amount increasing via NAMPT and nicotinamide mononucleotide adenylyl transferase (NMNAT), and reducing the proinflammatory, prooxidative and pro-apoptosis in RA patients [136].