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

“

TL;DR

This study investigated the role of 11β-HSD1, an enzyme that activates glucocorticoids, in muscle wasting during acute exacerbations of COPD using a mouse model. Contrary to the hypothesis that inhibiting 11β-HSD1 would protect against muscle loss, mice lacking 11β-HSD1 showed more severe muscle wasting than wild-type mice, driven by elevated circulating corticosterone levels and impaired muscle recovery mechanisms. These findings suggest that therapeutic 11β-HSD1 inhibitors may worsen rather than prevent muscle atrophy during acute COPD exacerbations, cautioning against their use in this clinical setting.

Full summary

4,414 CHARS

**Background:** Chronic obstructive pulmonary disease (COPD) is predicted to be the third leading cause of death worldwide by 2030. Skeletal muscle wasting is a severe extrapulmonary complication, particularly in emphysema patients, and is an independent predictor of mortality. Acute exacerbations of COPD (AE-COPD), typically triggered by infection, accelerate muscle loss. Glucocorticoids (GCs) such as cortisol are elevated during inflammation and contribute to muscle atrophy through activation of proteolytic pathways and suppression of anabolic signaling. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive GC precursors into active forms, amplifying GC signaling in peripheral tissues. Its expression is upregulated in muscle by proinflammatory mediators, hypoxia, and fasting. Although 11β-HSD1 inhibitors have been explored in Phase II trials for metabolic diseases, their role in muscle wasting during inflammatory diseases like COPD is poorly defined. This study aimed to determine whether 11β-HSD1 deletion could prevent GC-induced muscle wasting in AE-COPD.

**Methods:** Male WT and global 11β-HSD1 knockout (11βHSD1/KO) mice (aged 14–20 weeks, n=33) received two weekly intratracheal instillations of porcine pancreas elastase to induce emphysema, confirmed by micro-CT. Emphysematous mice were then randomly divided to receive either LPS (2 μg/g) or PBS intratracheally to evoke pulmonary inflammation. Animals were euthanized 48 hours post-LPS/PBS. Hind limb muscles were dissected, weighed, and analyzed for gene expression (RT-qPCR) and protein levels (Western blot). Plasma corticosterone and IL-6 were measured by ELISA. In vitro experiments used C2C12 myotubes and human primary myotubes to assess myonuclear accretion and GC effects.

**Key Results:** Both WT and 11βHSD1/KO mice developed comparable emphysema (LAA fold-change WT=1.5, p<0.001; KO=1.9, p<0.001) and similar body weight loss after LPS (−12% WT, −13% KO, both p<0.05). However, muscle wasting was more pronounced in 11βHSD1/KO mice: hind limb muscle mass decreased by −9.3% in KO vs. −3.4% in WT (p<0.0005). Gastrocnemius wet weight showed −13% reduction in KO (p<0.0001) vs. −7% in WT (p<0.005). Atrogin-1 mRNA increased 5.1-fold in KO (p<0.005) vs. 2.5-fold in WT (p<0.05). MuRF-1 tended to increase only in KO (3.2-fold, p=0.07). Autophagy markers showed suppressed catabolic signaling in WT but not KO: LC3BII/I ratio was significantly reduced in WT but not KO; ULK1 (Ser757) phosphorylation increased in WT (1.4-fold, p<0.05) but not KO (1.3-fold, p=0.193). Anabolic signaling was activated in WT but attenuated in KO: Akt phosphorylation increased significantly only in WT (1.5-fold, p<0.005); S6 phosphorylation increased significantly in WT (1.7-fold, p<0.005) but not KO (1.7-fold, p=0.112); 4E-BP1 hyper-phosphorylation increased in both (WT 2.9-fold, p<0.01; KO 4-fold, p<0.05). Plasma corticosterone was significantly elevated only in LPS-treated KO mice compared with WT controls (1.4-fold, p<0.05), and direct comparison showed KO levels 1.5-fold higher than WT (p<0.005). Muscle Gilz expression, a GC-responsive gene, increased only in KO (1.8-fold, p<0.05). In vitro, corticosterone (250 nM) and dexamethasone (10 μM) significantly inhibited myonuclear accretion (CORT 0.5-fold, p<0.05; DEX 0.3-fold, p<0.005).

**Clinical Implications:** This study demonstrates that global deletion of 11β-HSD1 paradoxically worsens muscle wasting during AE-COPD in mice, contrary to the hypothesis that inhibiting this enzyme would protect against GC-induced muscle atrophy. The aggravated wasting is associated with elevated circulating corticosterone levels, increased muscle GC signaling, sustained proteolytic gene expression, and impaired anabolic recovery mechanisms. These findings suggest that the loss of 11β-HSD1 disrupts negative feedback regulation of the HPA axis, leading to excessive endogenous GC exposure. The study cautions against the use of therapeutic 11β-HSD1 inhibitors in the setting of acute COPD exacerbations, as they may exacerbate rather than prevent muscle wasting. Limitations include the use of a global knockout model (not muscle-specific), the use of LPS as a single inflammatory trigger, and the need for direct protein synthesis measurements. Future studies using muscle-specific 11β-HSD1 knockout models could help disentangle local versus systemic effects.