SFEBES2023 Poster Presentations Metabolism, Obesity and Diabetes (70 abstracts)
The contribution of glucocorticoid metabolism by 11β-HSD1 towards muscle wasting in chronic kidney disease
Ben Cassidy 1 , Louise Firkins 1 , Michael Sagmeister 1 , Ana Crastin 1 , Gowsihan Poologasundarampillai 2 , Lorraine Harper 3 , Simon W. Jones 4 & Rowan S. Hardy 1
1IMSR, University of Birmingham, Birmingham, United Kingdom. 2Dentistry, University of Birmingham, Birmingham, United Kingdom. 3Applied Health Research University of Birmingham, Birmingham, United Kingdom. 4IIA, University of Birmingham, Birmingham, United Kingdom
Background: Skeletal muscle wasting is a characteristic feature of chronic kidney disease (CKD), associated with increased hospitalisations and premature mortality. Excess glucocorticoid signalling is a major contributor to the pathogenesis of muscle wasting in conditions of renal impairment. This study aimed to validate a murine model of CKD and utilise this to determine if deletion of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) provides protection against muscle atrophy.
Methods: 8-week-old male mice with wild-type (WT) or 11β-HSD1 knockout (11βKO) genetic background received either normal chow diet or chow treated with 0.15% adenine for 7-weeks to induce renal impairment. Model validation involved histological analysis of kidney tissue, measurement of urea and creatinine serum concentrations and inflammatory markers. The effects of 11βKO on skeletal muscle weights, fibre size distribution, steroid metabolism, catabolic pathways and inflammation were assessed ex vivo.
Results: Adenine induced increased urea and creatinine concentrations in both WT (fold changes 3.16 and 2.79, P<0.0001 respectively) and 11βKO mice (fold changes 4.69 and 4.10, P<0.0001 respectively) with reduced functional tissue (fold changes WT: 0.35; 11βKO: 0.22, P<0.0001). Adenine treatment led to reduced myofiber area (WT: -13.83%, P<0.05; 11βKO: -16.79%, P<0.01) with no protection observed in 11βKO mice. No significant changes were observed in markers of catabolic signalling or inflammation.
Conclusions: The Adenine diet model of CKD effectively induced renal impairment for both WT and 11βKO. This resulted coincided with marked muscle atrophy, mirroring observations in human disease. The metabolic, catabolic and inflammatory markers provided limited insight into the underpinning biochemistry. 11βKO offered no protective properties against skeletal muscle wasting.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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