Investigations into the integrated metabolism of glucocorticoids and glucose in skeletal muscle

Skeletal muscle plays a central role in maintaining metabolic homeostasis in health and disease. An important metabolic component of muscle is the integrated metabolism of glucose and glucocorticoids (GCs) in the lumen of the sarcoplasmic reticulum (SR). Glucose-6-phosphate (G6P) transported into the SR by the G6P transporter (G6PT) is metabolised by hexose-6-phosphate dehydrogenase (H6PDH) to produce nicotinamide adenine dinucleotide phosphate reduced (NADPH) cofactor that is utilised by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to reduce inactive GCs to their active forms. This thesis evaluated the SR unit as a site of integrated metabolism using a range of genetic models and screening methods. We demonstrate that perturbation of redox and metabolic balance through the distribution of H6PDH enzyme resulted in novel stress responses leading to shifts in redox and energy metabolism. Particularly, we show how the SR can elicit transcriptional changes that appear to adapt NADPH redox perturbation and also increase energy metabolism through augmented mitochondrial function. These data presented a novel sensing pathway within the SR unit that could have important relevance to metabolic and energetic control of skeletal muscle