Divergent roles of skeletal muscle 11β-HSD1 in age-related and chronic kidney disease-associated sarcopenia

BACKGROUND: Chronic kidney disease (CKD) is associated with increased incidence of sarcopenia and muscle weakness in aging patients. The glucocorticoid-activating enzyme11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within skeletal muscle in these patients has been implicated in driving this process. We hypothesized that skeletal muscle 11β-HSD1 is elevated in CKD and aging, where it would represent a promising therapeutic target. METHODS: We measured 11β-HSD1 activity in quadriceps biopsies from 17 CKD patients (eGFR <30 mL/min) and 14 age-matched controls (mean age 71 ± 5 years). Muscle strength, mass, and gait speed were assessed in relation to tissue 11β-HSD1 activity. Primary human myotubes were treated with patient-derived sera to evaluate regulatory drivers. Murine models of CKD (adenine diet) and aging (21 months) in wild-type (WT) and 11β-HSD1 knockout (11βKO) animals were examined to model therapeutic targeting. RESULTS: Muscle 11β-HSD1 activity was not elevated with CKD, but increased with age (r = 0.559, P = .001), predicting lower grip strength (P = .008). Markers of inflammation, including C-reactive protein and IL-6, strongly predicted 11β-HSD1 activity. Pro-inflammatory mediators such as TNFα directly upregulated 11β-HSD1 activity in myotubes, whilst sera from CKD donors did not. Whilst mice with 11βKO deletion were not protected from CKD-driven muscle atrophy, 11βKO animals showed marked protection against age-related muscle loss. CONCLUSIONS: Skeletal muscle 11β-HSD1 activity is not induced by CKD itself, but increases significantly over aging, where it is a predictor of muscle weakness. Its targeted deletion preserves muscle mass in aged mice, supporting its efficacy in preventing sarcopenia in an aging CKD population.