Nicotinic acid improves mitochondrial function and associated transcriptional pathways in older inactive males

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Abstract Objectives To examine the effect of the NAD+ precursor, nicotinic acid (NA), for improving skeletal muscle status in sedentary older people. Methods In a double-blind, randomised, placebo-controlled design, 18 sedentary yet otherwise healthy older (65–75 y) males were assigned to 2-weeks of NA (acipimox; 250 mg × 3 daily, n=8) or placebo (PLA, n=10) supplementation. At baseline, and after week 1 and week 2 of supplementation, a battery of functional, metabolic, and molecular readouts were measured. Results Resting and submaximal respiratory exchange ratio was lower (p<0.05) after 2 weeks in the NA group only, but maximal aerobic and anaerobic function and glucose handling were unchanged (p>0.05). Bayesian statistical modelling identified that leak, maximal coupled and maximal uncoupled mitochondrial respiratory states, increased over the 2-week supplemental period in the NA group (probability for a positive change (pd) 85.2, 90.8 and 95.9 %, respectively) but not in PLA. Citrate synthase and protein content of complex II (SDHB) and V (ATP5A) electron transport chain (ETC) components increased over the 2-week period in the NA group only (pd 95.1, 74.5 and 82.3 %, respectively). Mitochondrial and myofibrillar protein synthetic rates remained unchanged in both groups. NA intake altered the muscle transcriptome by increasing the expression of gene pathways related to cell adhesion/cytoskeleton organisation and inflammation/immunity and decreasing pathway expression of ETC and aerobic respiration processes. NAD+-specific pathways (e.g., de novo NAD+ biosynthetic processes) and genes (e.g., NADSYN1) were uniquely regulated by NA. Conclusions NA might be an effective strategy for improving ageing muscle mitochondrial health.