Nicotinamide mononucleotide supplementation mitigates osteopenia induced by modeled microgravity in rats.

Exposure to weightlessness causes severe osteopenia, resulting in raised fracture risk. The current study aimed to investigate whether nicotinamide mononucleotide (NMN) supplementation protected against the osteopenia in hindlimb unloading (HLU) rats in vivo and modeled microgravity-induced osteoblastic dysfunction in vitro. The 3-mo-old rats were exposed to HLU and intragastrically administered NMN every 3 days (500 mg/kg body weight) for 4 weeks. NMN supplementation mitigated HLU-induced bone loss, evidenced by greater bone mass and biomechanical properties and better trabecular bone structure. NMN supplementation mitigated HLU-induced oxidative stress, evidenced by greater levels of nicotinamide adenine dinucleotide and activities of superoxide dismutase 2 and lesser malondialdehyde levels. Modeled microgravity stimulation using rotary wall vessel bioreactor in MC3T3-E1 cells inhibited osteoblast differentiation, which was reversed by NMN treatment. Furthermore, NMN treatment mitigated microgravity-induced mitochondrial impairments, evidenced by lesser reactive oxygen species generation and greater adenosine triphosphate production, mtDNA copy number, and activities of superoxide dismutase 2 and Complex I and II. Additionally, NMN promoted activation of AMP-activated protein kinase (AMPK), evidenced by greater AMPKα phosphorylation. Our research suggested that NMN supplementation attenuated osteoblastic mitochondrial impairment and mitigated osteopenia induced by modeled microgravity.