Abstract
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.
Highlights
Glucocorticoids fulfil important permissive and adaptive roles in the regulation of skeletal muscle energy metabolism, impacting glucose utilization, insulin sensitivity, amino acid, and lipid metabolism.[1]
Intracellular glucocorticoid generation in skeletal muscle relies on the coordinate expression of the proteins G6P transporter (G6PT)/hexose‐ 6‐phosphate dehydrogenase (H6PDH)/11β‐HSD1
Hexose‐6‐phosphate dehydrogenase and G6PT expressions are fairly constant during postmuscle cell differentiation, suggesting that their levels are sufficient to facilitate maintenance of appropriate sarcoplasmic reticulum (SR) redox conditions, whereas 11β‐HSD1 expression and activity increase over differentiation and are further responsive to exogenous glucocorticoids
Summary
Glucocorticoids fulfil important permissive and adaptive roles in the regulation of skeletal muscle energy metabolism, impacting glucose utilization, insulin sensitivity, amino acid, and lipid metabolism.[1]. The role of 11β‐HSD1 in regulating muscle‐specific insulin signalling and lipid utilization has been established.12,13 11β‐Hydroxysteroid dehydrogenase type 1 expression and activity are elevated in type 2 diabetic muscles, and so 11β‐HSD1 inhibition may offer potential to enhance insulin sensitivity.[12] not all 11β‐HSD1 knockout (HSD1KO) loss‐of‐function models have demonstrated protection from metabolic disease and suggest that use of inhibitors will need to be tailored to specific pathologies.[14,15] it has been shown that 11β‐HSD1KO mice are almost completely protected from the deleterious metabolic effects of glucocorticoid excess, and inhibition in this scenario may be truly beneficial.[3,12,13,16]. It is envisaged that these data will permit a more thorough appreciation of their muscle‐specific functions in the context of glucocorticoid excess and metabolic disease
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