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Glucocorticoids are important for skeletal muscle energy metabolism, regulating glucose utilization, insulin sensitivity, and muscle mass. Nicotinamide adenine dinucleotide phosphate-dependent 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-mediated glucocorticoid activation in the sarcoplasmic reticulum (SR) is integral to mediating the detrimental effects of glucocorticoid excess in muscle. 11β-Hydroxysteroid dehydrogenase type 1 activity requires glucose-6-phosphate transporter (G6PT)-mediated G6P transport into the SR for its metabolism by hexose-6-phosphate dehydrogenase (H6PDH) for NADPH generation. Here, we examine the G6PT/H6PDH/11β-HSD1 triad in differentiating myotubes and explore the consequences of muscle-specific knockout of 11β-HSD1 and H6PDH. 11β-Hydroxysteroid dehydrogenase type 1 expression and activity increase with myotube differentiation and in response to glucocorticoids. Hexose-6-phosphate dehydrogenase shows some elevation in expression with differentiation and in response to glucocorticoid, while G6PT appears largely unresponsive to these particular conditions. When examining 11β-HSD1 muscle-knockout mice, we were unable to detect significant decrements in activity, despite using a well-validated muscle-specific Cre transgene and confirming high-level recombination of the floxed HSD11B1 allele. We propose that the level of recombination at the HSD11B1 locus may be insufficient to negate basal 11β-HSD1 activity for a protein with a long half-life. Hexose-6-phosphate dehydrogenase was undetectable in H6PDH muscle-knockout mice, which display the myopathic phenotype seen in global KO mice, validating the importance of SR NADPH generation. We envisage these data and models finding utility when investigating the muscle-specific functions of the 11β-HSD1/G6PT/H6PDH triad., (Copyright © 2017 John Wiley & Sons, Ltd.)

Hexose-6-phosphate dehydrogenase (H6PDH) has emerged as an important factor in setting the redox status of the endoplasmic reticulum (ER) lumen. An important role of H6PDH is to generate a high NADPH/NADP(+) ratio which permits 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to act as an oxo-reductase, catalyzing the activation of glucocorticoids (GCs). In H6PDH knockout mice 11β-HSD1 assumes dehydrogenase activity and inactivates GCs, rendering the target cell relatively GC insensitive. Consequently, H6PDHKO mice have a phenotype consistent with defects in the permissive and adaptive actions of GCs upon physiology. H6PDHKO mice have also offered an insight into muscle physiology as they also present with a severe vacuolating myopathy, abnormalities of glucose homeostasis and activation of the unfolded protein response due to ER stress, and a number of mechanisms driving this phenotype are thought to be involved. This article will review what we understand of the redox control of GC hormone metabolism regulated by H6PDH, and how H6PDHKO mice have allowed an in-depth understanding of its potentially novel, GC-independent roles in muscle physiology., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)