Endocrine Abstracts (2009) 19 OC12

Absence of hexose-6-phosphate dehydrogenase specifically induces skeletal myopathy in mice

N Semjonous, G Lavery, E Walker & P Stewart

University of Birmingham, Birmingham, UK.

Murine 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses the conversion of inactive 11-dehydrocorticosterone (A) to active corticosterone (B) and plays a key role in metabolic homeostasis. The directionality of this enzyme is dependent upon the presence of NADPH, a cofactor produced by hexose-6-phosphate dehydrogenase (H6PDH). In accord with this, H6PDH KO mice have no reductase and increased dehydrogenase activity of 11βHSD1. Interestingly, H6PDH KO mice also unexpectedly display a severe skeletal myopathy, characterised by the switching of type 2 to type 1 muscle fibres as a result of endoplasmic reticulum (ER) stress. However, it is not known whether this myopathy is either a direct effect of H6PDH or a result of increased dehydrogenase activity of 11βHSD1. To determine this we have generated a 11βHSD1 H6PDH double KO (DKO) mouse. Urine samples were analysed by GC/MS for steroid metabolites and 11βHSD1 activity was measured using a liver explant model. RNA was isolated from liver and quadricep muscle and gene expression for HSPa5, DDIT3 and AMPD1 were determined by real-time PCR. DKO mice displayed characteristics indicative of a lack of 11βHSD1. Low or undetectable levels of 11βHSD1 activity were demonstrated in DKO mouse liver explants, whilst urinary metabolites were similar to those of 11βHSD1 KO mice: % corticosterone metabolites 96.1% (WT), 67.8% (11βHSD1 KO), 58.3% (DKO). In the muscle of DKO mice, gene expression abnormalities similar to H6PDH KO mice were observed. ER stress genes HSPa5 and DDIT3 were up-regulated 14- and 30-fold respectively in DKO mice. Furthermore, expression of AMPD1, a gene commonly associated with myopathy in humans, was down-regulated 10-fold. In conclusion, DKO mice exhibit a skeletal myopathy similar to that of the H6PDH KO mouse. These studies suggest that this myopathy is specifically due to a lack of H6PDH, supporting a novel role for this enzyme in skeletal muscle function.

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