Hormonal regulation of skeletal muscle metabolism

Nicotinamide Adenine Dinucleotide (NAD+) is a cofactor for enzymes serving cellular metabolic reactions and a consumed substrate for sirtuins and poly (adenosine diphosphate-ribose) polymerases (PARPs), enzymes that regulate protein deacetylation and DNA repair, and translate changes in energy and cell status into metabolic adaptations. Deranged NAD+ homeostasis and concurrent mitochondrial dysfunction are key features of ageing and age-related metabolic disease. Contemporary NAD+ precursors (vitamin B3 derivatives) showed promise as therapeutic nutraceuticals to restore target tissue NAD+ in at risk groups and have demonstrated improvements in mitochondrial function and sirtuin-dependent signalling in pre-clinical studies. We conducted the NADMet (Nicotinamide Adenine Dinucleotide and Skeletal Muscle Metabolic Phenotype) clinical study to examine whether NAD+ can be increased in human tissues using oral nutraceutical approaches and assess for a potential role in combating metabolic disease and the unwanted effects of ageing. The results showed that the oral supplementation of the NAD+ precursor, nicotinamide riboside, in aged men was safe and well-tolerated leading to an increase in the skeletal muscle NAD+ metabolome and induced a specific transcriptomic signature without altering muscle specific or systemic metabolism. NAD+ is also a parent molecule for NADPH which is a cofactor for the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme that regenerates glucocorticoids in the sarcoplasmic reticulum (SR) of skeletal muscle. The maintenance of the SR NADPH/NADP+ ratio is poorly understood. This work suggests a novel level of regulated glucocorticoid metabolism in skeletal muscle whereby 11β-HSD1 activity can be influenced by cellular redox status and NAD+ levels beyond the SR.