Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham UK, B15 2TT, United Kingdom.
Endocrinology. 2011 Jan;152(1):93-102. doi: 10.1210/en.2010-0957. Epub 2010 Nov 24.
Glucose-6-phosphate (G6P) metabolism by the enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the sarcoplasmic reticulum lumen generates nicotinamide adenine dinucleotide phosphate (reduced) to provide the redox potential for the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to activate glucocorticoid (GC). H6PDH knockout (KO) mice have a switch in 11β-HSD1 activity, resulting in GC inactivation and hypothalamic-pituitary-adrenal axis activation. Importantly, H6PDHKO mice develop a type II fiber myopathy with abnormalities in glucose metabolism and activation of the unfolded protein response (UPR). GCs play important roles in muscle physiology, and therefore, we have examined the importance of 11β-HSD1 and GC metabolism in mediating aspects of the H6PDHKO myopathy. To achieve this, we examined 11β-HSD1/H6PDH double-KO (DKO) mice, in which 11β-HSD1 mediated GC inactivation is negated. In contrast to H6PDHKO mice, DKO mice GC metabolism and hypothalamic-pituitary-adrenal axis set point is similar to that observed in 11β-HSD1KO mice. Critically, in contrast to 11β-HSD1KO mice, DKO mice phenocopy the salient features of the H6PDHKO, displaying reduced body mass, muscle atrophy, and vacuolation of type II fiber-rich muscle, fasting hypoglycemia, increased muscle glycogen deposition, and elevated expression of UPR genes. We propose that muscle G6P metabolism through H6PDH may be as important as changes in the redox environment when considering the mechanism underlying the activation of the UPR and the ensuing myopathy in H6PDHKO and DKO mice. These data are consistent with an 11β-HSD1-independent function for H6PDH in which sarcoplasmic reticulum G6P metabolism and nicotinamide adenine dinucleotide phosphate-(oxidized)/nicotinamide adenine dinucleotide phosphate (reduced) redox status are important for maintaining muscle homeostasis.
葡萄糖-6-磷酸（G6P）通过肌浆网腔中的己糖激酶 6 磷酸脱氢酶（H6PDH）代谢，生成烟酰胺腺嘌呤二核苷酸磷酸（还原型），为 11β-羟类固醇脱氢酶 1 型（11β-HSD1）酶提供氧化还原电位，使糖皮质激素（GC）激活。H6PDH 敲除（KO）小鼠的 11β-HSD1 活性发生转换，导致 GC 失活和下丘脑-垂体-肾上腺轴激活。重要的是，H6PDHKO 小鼠发展为 II 型纤维肌病，伴有葡萄糖代谢异常和未折叠蛋白反应（UPR）激活。GC 在肌肉生理学中发挥重要作用，因此，我们研究了 11β-HSD1 和 GC 代谢在介导 H6PDHKO 肌病方面的重要性。为了实现这一目标，我们检查了 11β-HSD1/H6PDH 双敲除（DKO）小鼠，其中 11β-HSD1 介导的 GC 失活被否定。与 H6PDHKO 小鼠相反，DKO 小鼠的 GC 代谢和下丘脑-垂体-肾上腺轴基准与 11β-HSD1KO 小鼠观察到的相似。至关重要的是，与 11β-HSD1KO 小鼠相比，DKO 小鼠表现出 H6PDHKO 的显著特征，表现为体重减轻、肌肉萎缩和富含 II 型纤维的肌肉空泡化、空腹低血糖、肌肉糖原沉积增加和 UPR 基因表达升高。我们提出，考虑到 UPR 激活和随后的 H6PDHKO 和 DKO 小鼠肌病的机制，通过 H6PDH 的肌肉 G6P 代谢可能与氧化还原环境的变化一样重要。这些数据与 H6PDH 的 11β-HSD1 独立功能一致，其中肌浆网 G6P 代谢和烟酰胺腺嘌呤二核苷酸磷酸（氧化型）/烟酰胺腺嘌呤二核苷酸磷酸（还原型）氧化还原状态对于维持肌肉内稳态很重要。
