11b-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD

Muscle atrophy is an extrapulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 13-hydroxysteroid dehydrogenase 1 (1113-HSD1) activates GCs and contributes toward GC-induced muscle wasting. To explore the potential of 1113HSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 1113HSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intratracheal (IT) instillation of elastase to model COPD in WT and 1113HSD1/KO mice, fol-lowed by vehicle or IT-LPS administration to mimic AE. mu CT scans were obtained prior and at study endpoint 48 h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were deter-mined by ELISA. In vitro, myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-1113HSD1/KO animals compared with WT controls. RT-qPCR and west-ern blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-1113HSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-1113HSD1/KO animals, whereas C2C12 myotubes treated with LPS-1113HSD1/ KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 1113-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 1113-HSD1 may not be appropriate to prevent muscle wasting in this setting.