Abstract: FR-PO1205
Evaluation of Glucocorticoid Metabolism in CKD as a Therapeutic Target against Sarcopenia
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Sagmeister, Michael S., University of Birmingham College of Medical and Dental Sciences, Birmingham, United Kingdom
- Crastin, Ana, University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
- Taylor, Angela E., University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
- Jones, Simon W., University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
- Harper, Lorraine, University of Birmingham College of Medical and Dental Sciences, Birmingham, United Kingdom
- Hardy, Rowan S., University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, United Kingdom
Background
Skeletal muscle loss and weakness, termed sarcopenia, has been linked to dysregulation of glucocorticoid hormones in CKD. Glucocorticoid excess is favoured by loss of the renal enzyme 11β-hydroxysteroid dehydrogenase (11βHSD) type 2 that inactivates cortisol to cortisone. The cortisol-activating counterpart, 11βHSD type 1, which is upregulated in skeletal muscle in response to inflammation, has not yet been investigated in this context. This study tests whether raised glucocorticoid activation by 11βHSD1 in skeletal muscle contributes to sarcopenia in CKD and represents a novel therapeutic target.
Methods
An observational study recruited 17 patients with pre-dialysis CKD (eGFR <30) and 14 healthy volunteers aged 60-80 years. Muscle phenotype was assessed by bio-impedance body composition, grip strength and short physical performance battery. Steroid hormones were measured in early morning serum and 24-hour urine by liquid chromatography/mass spectrometry. The rate of enzymatic cortisol activation by 11βHSD1 in muscle was determined in vastus lateralis biopsies ex vivo. Using the adenine mouse model of renal impairment, an animal experiment examined the therapeutic potential of 11βHSD1 suppression to protect against muscle atrophy.
Results
Serum cortisol is similar in CKD, while serum cortisone is reduced relative to healthy controls (p<0.0001). Serum cortisol or 24-hour urinary glucocorticoid excretion are not associated with skeletal muscle mass or strength. In contrast, 11βHSD1 enzymatic activity in skeletal muscle correlates negatively with muscle strength independent of age and gender (p=0.002). Despite its association with muscle strength, 11βHSD1 activity is not significantly different between patients with CKD and healthy volunteers. In the mouse model of renal impairment, genetic silencing of 11βHSD1 fails to improve skeletal muscle atrophy.
Conclusion
Low muscle strength correlates with cortisol activation by 11βHSD1 in skeletal muscle. However, renal impairment by itself does not alter 11βHSD1 function in muscle, and 11βHSD1 suppression does not prevent muscle atrophy in a mouse model of CKD. Future studies may explore to what extent glucocorticoids contribute to sarcopenia in human CKD through alternative mechanisms, or whether 11βHSD1 is significant for sarcopenia development in settings unrelated to CKD.
Funding
- Government Support – Non-U.S.