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 hypothesised 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=0.001), predicting lower grip strength (p=0.008). 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.