Endocrine Abstracts

Introduction: Muscle atrophy is a major clinical complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates glucocorticoids (GCs) within muscle, is induced by inflammation, and has been shown to contribute towards GC-induced muscle wasting. In this study, we examined the role of 11β-HSD1 in this context using a murine model of COPD-AE in animals with transgenic global deletion of 11β-HSD1.

Methods: WT and 11β-HSD1/KO mice received two intra-tracheal (IT) instillations of elastase to induce stable emphysema (COPD), followed by a single bolus of IT-LPS to mimic AE, or vehicle. After 48 hours muscle, serum and lung tissues were collected. μCT scans were collected prior and following IT-LPS, to assess emphysema progression and muscle mass changes, respectively. Anabolic, catabolic and inflammatory gene and protein expression were examined by RT-qPCR and western blot. Serum corticosterone was determined by ELISA. in vitromyonuclear accretion in response to serum and GCs was determined in C2C12.

Results: Comparable emphysema progression was observed in both WT and 11β-HSD1/KO animals.Muscle wasting was exacerbated in 11β-HSD1/KO COPD-AE animals compared to WT controls characterised by reduced gastrocnemius muscle wet weights and total leg muscle by μCT. Catabolic pathways, including Atrogin-1 and MuRF-1 were elevated in 11β-HSD1/KO COPD-AE animals relative to WTs, whilst anabolic and anti-catabolic pathways such as p-S6 (S235/236) and p-FoxO1 (S256) were suppressed. Serum corticosterone levels were significantly higher in 11β-HSD1/KO COPD-AE animals relative to compared to WT, whilst C2C12 myotubes treated with 11β-HSD1/KO COPD-AE plasma or exogenous GCs had a reduced capacity for myonuclear accretion relative to WT counterparts.

Conclusions: These findings demonstrate 11β-HSD1 determines the extent of muscle wasting during acute exacerbation of COPD. Here, transgenic deletion of 11β-HSD1 drives dysregulation of circulating corticosteroids and muscle metabolism, favouring increased catabolic and decreased anabolic responses.