Hexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis independent of 11β-hydroxysteroid dehydrogenase type 1.

Hdl Handle:
http://hdl.handle.net/10147/253943
Title:
Hexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis independent of 11β-hydroxysteroid dehydrogenase type 1.
Authors:
Semjonous, Nina M; Sherlock, Mark; Jeyasuria, Pancharatnam; Parker, Keith L; Walker, Elizabeth A; Stewart, Paul M; Lavery, Gareth G
Affiliation:
Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham UK, B15 2TT, United Kingdom.
Citation:
Hexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis independent of 11β-hydroxysteroid dehydrogenase type 1. 2011, 152 (1):93-102 Endocrinology
Publisher:
Endocrinology
Journal:
Endocrinology
Issue Date:
Jan-2011
URI:
http://hdl.handle.net/10147/253943
DOI:
10.1210/en.2010-0957
PubMed ID:
21106871
Abstract:
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.
Item Type:
Article
Language:
en
MeSH:
11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Blood Glucose; Carbohydrate Dehydrogenases; Corticosterone; Gene Expression Regulation, Enzymologic; Homeostasis; Insulin; Mice; Mice, Knockout; Muscle, Skeletal; Muscular Diseases
ISSN:
1945-7170

Full metadata record

DC FieldValue Language
dc.contributor.authorSemjonous, Nina Men_GB
dc.contributor.authorSherlock, Marken_GB
dc.contributor.authorJeyasuria, Pancharatnamen_GB
dc.contributor.authorParker, Keith Len_GB
dc.contributor.authorWalker, Elizabeth Aen_GB
dc.contributor.authorStewart, Paul Men_GB
dc.contributor.authorLavery, Gareth Gen_GB
dc.date.accessioned2012-11-29T15:33:25Z-
dc.date.available2012-11-29T15:33:25Z-
dc.date.issued2011-01-
dc.identifier.citationHexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis independent of 11β-hydroxysteroid dehydrogenase type 1. 2011, 152 (1):93-102 Endocrinologyen_GB
dc.identifier.issn1945-7170-
dc.identifier.pmid21106871-
dc.identifier.doi10.1210/en.2010-0957-
dc.identifier.urihttp://hdl.handle.net/10147/253943-
dc.description.abstractGlucose-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.en_GB
dc.language.isoenen
dc.publisherEndocrinologyen_GB
dc.rightsArchived with thanks to Endocrinologyen_GB
dc.subject.mesh11-beta-Hydroxysteroid Dehydrogenase Type 1-
dc.subject.meshAnimals-
dc.subject.meshBlood Glucose-
dc.subject.meshCarbohydrate Dehydrogenases-
dc.subject.meshCorticosterone-
dc.subject.meshGene Expression Regulation, Enzymologic-
dc.subject.meshHomeostasis-
dc.subject.meshInsulin-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMuscle, Skeletal-
dc.subject.meshMuscular Diseases-
dc.titleHexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis independent of 11β-hydroxysteroid dehydrogenase type 1.en_GB
dc.typeArticleen
dc.contributor.departmentCentre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham UK, B15 2TT, United Kingdom.en_GB
dc.identifier.journalEndocrinologyen_GB
dc.description.provinceLeinsteren

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