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

Deane, Colleen S.; Willis, Craig R. G.; Gallagher, Iain J.; Brook, Matthew S.; Gharahdaghi, Nima; Wylie, Lee J.; Wilkinson, Daniel J.; Smith, Kenneth; Atherton, Philip J.; Etheridge, Timothy

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.

Citation

Deane, C. S., Willis, C. R. G., Gallagher, I. J., Brook, M. S., Gharahdaghi, N., Wylie, L. J., Wilkinson, D. J., Smith, K., Atherton, P. J., & Etheridge, T. (in press). Nicotinic acid improves mitochondrial function and associated transcriptional pathways in older inactive males. Translational Exercise Biomedicine, 1(3-4), 277-294. https://doi.org/10.1515/teb-2024-0030

• Journal Article Type: Article
• Acceptance Date: Oct 30, 2024
• Online Publication Date: Nov 25, 2024
• Deposit Date: Jan 8, 2025
• Publicly Available Date: Jan 8, 2025
• Journal: Translational Exercise Biomedicine
• Print ISSN: 2942-6812
• Publisher: De Gruyter
• Peer Reviewed: Peer Reviewed
• Volume: 1
• Issue: 3-4
• Pages: 277-294
• DOI: https://doi.org/10.1515/teb-2024-0030
• Keywords: NAD+, mitochondria, acipimox, ageing, skeletal muscle, nicotinic acid