Effect of Dietary Nicotinamide Mononucleotide (NMN) on Function and Mechanics of Skeletal Muscle Arteries from Aged Mice

Abstract

Ageing is associated with a decline in vascular function and increased risk of cardiovascular disease. Dietary NMN, an NAD+ precursor, increases muscle vascularity, blood flow and exercise performance in aged mice 1. This study determined the effects of dietary NMN on endothelium‐dependent dilation (EDD) and vascular stiffness in skeletal muscle arteries isolated from aged mice. Male and female C57BL/6J mice received NMN (400 mg/kg) in drinking water for 8–10 weeks; mice were ~97 weeks old at the end of the treatment period. Segments of the saphenous and gracilis muscle arteries (SA and GMA respectively) were removed. Functional responses were examined using pressure myography. SA and some GMA were pre‐constricted with phenylephrine. Pressure‐induced myogenic tone was enhanced in GMA from NMN‐treated male mice. NMN treatment enhanced EDD in the GMA of both male and female mice as measured by a leftward shift in the pEC50 of acetylcholine concentration‐response curves. EDD in the SA from either sex was not altered by NMN treatment. NMN treatment also did not affect responses to the endothelium‐independent vasodilator sodium nitroprusside in either artery, from either sex. The nitric oxide synthase (NOS) inhibitor L‐NAME (100 μM) strongly inhibited EDD in the SA but caused only minor inhibition of EDD in the GMA, from both sexes. In the GMA from both sexes, EDD was significantly inhibited by blockers of Ca2+‐sensitive K+ channels (KCa). Analysis of relative EC50‐shift suggested intermediate‐conductance‐KCa (IKCa)‐mediated vasodilation was enhanced in the GMA from NMN‐treated mice. Stress‐strain relationships were obtained from arteries under passive conditions, over the pressure‐range 5–120 mmHg. Analysis of these relationships showed NMN treatment increased compliance of GMA, but not SA, from both sexes. SA from female mice were less compliant than SA from male mice, regardless of NMN treatment. These studies suggest NMN treatment can enhance EDD, decrease arterial stiffness and improve blood flow autoregulation in small resistance (GMA) arteries, but not larger conduit (SA) arteries in skeletal muscle from aged mice. The increased EDD may be due to increased IKCa‐mediated vasodilation, but not increased nitric oxide‐mediated effects. These changes may contribute to the enhanced muscle blood flow and exercise performance observed in aged NMN‐treated mice.