Endocrine Abstracts

Introduction: Glucocorticoid excess (GE) causes severe metabolic dysfunction within skeletal muscle (SM) which includes reduced muscle accrual and increased proteolysis. The NAD+ metabolome is crucial for SM health and metabolic function, however, whether this is disrupted by GE remains unknown.

Methods: Male and female C57BL/6J mice (n=12) were treated with a vehicle control or corticosterone (100 mg/l) ad libitum via drinking water for 3 weeks to induce a phenotype typical of GE. SM samples were analysed using NMR and qPCR to assess the impact on the NAD+ metabolome.

Results: Corticosterone treatment reduced SM accrual as assessed by tissue weight. Corticosterone treatment decreased SM NAD+ in both males and females (-78.7±3.1% and -8.8±2.3%), as assessed by NMR. The NAD+ breakdown product and precursor, nicotinamide (NAM) was similarly decreased in males and females (-73.3±1.8% and -56.7±1.3%). The gene expression of some of the enzymes involved in SM NAD+ biosynthesis was altered, as assessed by qPCR. Corticosterone increased expression of the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) (16.0±11.3% and 18.3±13.0%) and decreased expression of nicotinamide riboside kinase 2 (-50.7±35.8% and -7.63±19.5%) in males and females. In males only it decreased nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) expression (-6.2±4.4%). No other alterations to gene expression were observed.

Conclusion: These findings provide evidence that the SM NAD+ metabolome is disrupted by GE in male and female C57BL/6J mice. This includes a decrease in NAD+ and NAM content, as well as some alterations to the gene expression of enzymes involved in SM NAD+ biosynthesis. Whether this is a contributing factor to SM dysfunction associated with glucocorticoid excess remains to be determined. Further analysis of the NAD+ metabolome is required, including assessment of the reduced form of NAD+, NADH, and the NAD+/NADH ratio, both of which are metabolically important.