Abstract
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 β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs and contributes toward GC-induced muscle wasting. To explore the potential of 11βHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11βHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intratracheal (IT) instillation of elastase to model COPD in WT and 11βHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. μCT 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 determined 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-11βHSD1/KO animals compared with WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11βHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11βHSD1/KO animals, whereas C2C12 myotubes treated with LPS-11βHSD1/ KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11β-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11β-HSD1 may not be appropriate to prevent muscle wasting in this setting.
Original language | English |
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Pages (from-to) | L400-L412 |
Number of pages | 13 |
Journal | American Journal of Physiology-Lung Cellular and Molecular Physiology |
Volume | 324 |
Issue number | 4 |
DOIs | |
Publication status | Published - 1 Apr 2023 |
Keywords
- 11 b-hydroxysteroid dehydrogenase type 1
- COPD
- glucocorticoids
- inflammation
- muscle atrophy
- OBSTRUCTIVE PULMONARY-DISEASE
- DEHYDROGENASE TYPE-1 INHIBITOR
- C-REACTIVE PROTEIN
- SYSTEMIC INFLAMMATION
- TRANSLATION INITIATION
- UBIQUITIN LIGASES
- IGF-I
- GLUCOCORTICOIDS
- 11-BETA-HSD1
- EXPRESSION