Endocrine Abstracts

Background: Therapeutic glucocorticoids (GCs) are anti-inflammatory steroids that remain a cornerstone in the treatment of inflammatory kidney disease. However, off-target side effects including muscle atrophy and metabolic dysfunction limit their application. The enzyme 11β-HSD1 regulates the pre-receptor metabolism and amplification of GCs, influencing their peripheral side effects in tissues such as muscle. This study investigated the influence of 11β-HSD1 on muscle wasting related to GC therapy in the specific context of a murine model of kidney disease.

Methods: Male wild-type (WT) and 11β-HSD1 global knockout (11βKO) transgenic mice received 0.15 % adenine diet over 5 weeks to produce sustained renal injury. At week three, animals were additionally treated with the GC corticosterone in drinking water (100 mg/l) or vehicle control (0.6% ethanol) for a period of two weeks. Animals were culled at week 5, and serum, kidney, and muscle (quadriceps, tibialis anterior, soleus) collected. Renal impairment was assessed via serum markers (urea, creatinine) and histopathology. Lean muscle weight and fibre size were assessed, and markers of catabolic metabolism determined by qRT-PCR.

Results: The adenine diet resulted in comparable renal impairment in both WT and 11β-HSD1 KO mice. This was characterised by tubular damage and fibrosis, and elevated levels of serum urea and creatinine. Corticosteroid treatment improved renal inflammation and function in adenine-fed WT animals, but resulted in reduced quadriceps and tibialis-anterior weights and fiber size, with a marked increase in catabolic mediators such as Foxo1 and Fbxo32. In contrast, 11β-HSD1 KO mice were protected against corticosteroid-induced muscle atrophy.

Conclusion: These data indicate that targeted inhibition of 11β-HSD1 KO has the potential to ameliorate off-target side effects in muscle caused by therapeutic glucocorticoids in the setting of experimental renal injury. Further research will focus on muscle-specific targeting of 11β-HSD1 inhibition and validating translational potential in humans.