Glucocorticoid regulation of NAD+ and energy metabolism in skeletal muscle ageing

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Background and need for the projectGlucocorticoid hormones are regulators of muscle energy homeostasis, and in mild excess or deficiency lead to metabolic disease, particularly in muscle, contributing to age-related frailty and cardiovascular disease. The role of NAD+ as a metabolic cofactor in redox reactions is well understood, and impaired NAD+ synthesis or increased consumption is proposed to drive aspects of age-related functional deficits, particularly in muscle. It has been shown that using NAD+ precursors to augment the NAD+ metabolome can modify metabolism and positively impact on mitochondrial function and inflammation. Glucocorticoids interact with the NAD+ metabolome and synthetic pathways in muscle, but the nature and impact of this interaction on age-related metabolic dysregulation has not been studied. It is proposed that interrogation of this new axis of metabolic regulation will illuminate novel muscle biology and therapies in a range of age-related disease processes.HypothesisGlucocorticoid hormone and NAD+ synthesis and consumption pathways interact to modulate energy metabolism in ageing muscle through metabolic and transcriptional control of networks important to health.Aims and objectives1) Define muscle metabolic network dynamics and pathway signalling in response to glucocorticoid and NAD+.2) Investigate this network and its modulation with ageing in mouse models of altered NAD and glucocorticoid metabolism.3) Examine NAD dynamics, sensitivity and interactions with glucocorticoid in young and aged humans.Brief experimental planAim-1 and 2- To investigate glucocorticoid interaction with NAD+ pathways using primary mouse myotubes, mice with and without mild and chronic excess or deficiency e.g. CRH KO, young and aged mouse models with genetic modifications of NAD+ synthetic pathways (NMRK1/2KO, NAMPTKO, NMR2.Tg overexpression) in combination with state-of-the-art methodologies [e.g. NAD+ metabolome; expression and activity of the NAD+ biosynthetic programme; targeted proteomics; high resolution mitochondrial respiration; metabolomics; stable isotope (C13 glucose and palmitate, N15 glutamine) tracing of nutrient metabolism.Aim 3- To test whether metabolism deteriorates in response to glucocorticoid more readily in ageing humans and examine the role of NAD in this process, young and aged humans will be exposed to conditions of mild glucocorticoid excess (using oral prednisolone) with and without supplementation with NR to assess its effects on fasting, postprandial and exercise metabolism. This will be carried by examining muscle and adipose biopsy, adipose micro-dialysis, blood and urine samples. This aim will benefit from close collaboration with Professor Jeremy Tomlinson at the University of Oxford- a world renowned steroid biologist and clinician with expertise in the metabolic understanding of glucocorticoid hormone action in health and disease.Expected outcome- Mechanistic and physiological knowledge of glucocorticoid interactions with the NAD+ metabolic network in muscle in young and aged mice and humans.- Insight into the therapeutic potential of nutritional NAD+ boosting to augment muscle metabolic responses and function in young and aged mice and humans.- Student to receive advanced training in state-of-the-art integrative physiology in laboratories with reputations for strong mentorship, onward career development and impactful contributions to the literature.