Nicotinamide Mononucleotide Does Not Prevent Cardiac Hypertrophy but Attenuates Cardiac Stress and Remodeling Markers in Mice Exposed to Intermittent Normobaric Hypoxia

Abstract

Background: Nicotinamide mononucleotide (NMN) is a naturally occurring, biologically active nucleotide that serves as a crucial NAD+ precursor in various physiological conditions. Although intermittent hypoxia is known to substantially induce various health problems, whether NMN protects against injury induced by intermittent normobaric hypoxia remains unclear. Methods: In this study, mice were randomly assigned to groups under normoxia, intermittent normobaric hypoxia, and hypoxia with NMN intervention, and the effects of NMN were evaluated by examining organ indices, hematology, histopathology, and 16S rRNA gene amplicon sequencing. Results: Intermittent normobaric hypoxia significantly increased heart weight, cardiac index, right ventricular weight and index, spleen index, serum lactate dehydrogenase activity, and the cardiac expression of BNP and Myh7, indicating pathological cardiac hypertrophy and activation of a ventricular stress response. It also reduced the beta diversity of the gut microbiota and altered its composition. Although NMN intervention did not significantly affect most organ or hematological indices, except for a further increase in serum LDH activity, it significantly attenuated the hypoxia-induced expression of BNP and Myh7 in the right ventricle, restored the spleen weight and index, and changed the composition of the gut microbiota. These exploratory results indicate that NMN does not prevent intermittent normobaric hypoxia-induced cardiac hypertrophy at the organ level but mitigates cardiac stress markers, ameliorates splenic changes, and modulates the gut microbiota. Conclusions: These findings suggest that NMN produced selective molecular and systemic effects under hypoxic exposure rather than an overall protective phenotype and warrant further investigation.