SUN-488 Activin Type II Receptor Blockade Impacts on Muscle Wasting in Glucocorticoid-Treated Exacerbations of COPD

Abstract Disclosure: S.J. van Krimpen: None. J.M. Webster: None. P. Qiu: None. P. Henrot: None. B. Rezaeifar: None. S.O. Simons: None. A.M. Schols: None. R.C. Langen: None. H.R. Gosker: None. Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease worldwide. Muscle wasting is a well-known, extrapulmonary complication of COPD that negatively affects clinical outcomes. It is accelerated by exacerbations of COPD (ECOPD), which are defined as an acute worsening in respiratory symptoms over ≤ 14 days and is often associated with increased local and systemic inflammation. Synthetic glucocorticoids (GCs) are administered as standard-of-care (SOC) anti-inflammatory treatment to prevent clinical deterioration in individuals with ECOPD. However, GCs may aggravate the ECOPD-associated muscle wasting through their catabolic actions. As the latter partly rely on GC-induced myostatin signaling, we hypothesized that blocking activin type IIB receptor (ActIIB-R) to prevent myostatin signaling, attenuates muscle wasting in a mouse model of GC-treated ECOPD, thereby aiming to improve the overall therapeutic efficacy of GCs in ECOPD. Emphysema was induced in male C57BL/6J mice (n=12/group) by 3 weekly intratracheal (IT) instillations of elastase to model COPD, followed by IT-LPS (or vehicle) administration to evoke pulmonary inflammation. Dexamethasone (DEX, a GC) or vehicle was injected subcutaneously daily as SOC treatment in ECOPD, starting 4 hours after LPS. CDD866 (ActIIB-R blocking antibody, provided by Versanis Bio, 20 mg/kg bw) or vehicle was injected subcutaneously at the same time as the first DEX dose. Micro cone beam CT scans were performed weekly and at study endpoint (48 hours after LPS) to verify emphysema development and measure muscle volume changes. After sacrifice, hindlimb muscles were weighed and snap-frozen for further analysis. Compared to control, body weight change of GC-ECOPD was lower (-6.4%, p<0.001) whereas body weight change of GC-ECOPD/CDD866 was not. GC-ECOPD was not different from GC-ECOPD/CDD866. Muscle weight was reduced in GC-ECOPD compared to control (-6.7%, p<0.01), but not in GC-ECOPD/CDD866. GC-ECOPD muscle weight was not different from GC-ECOPD/CDD866. Preliminary analysis of right hindlimb muscle volume change showed no significant difference of GC-ECOPD or GC-ECOPD/CDD866 compared to control (-6.6% and +0.7% respectively, compared to -1.8%). Compared to GC-ECOPD, muscle volume change of GC-ECOPD/CDD866 was significantly higher (+0.7% vs -6.6%, p<0.05). Atrogene expression was not increased in GC-ECOPD compared to control but tended to decrease in GC-ECOPD/CDD866 compared to GC-ECOPD (Atrogin-1: p=0.053; MuRF1: 0.076). In conclusion, in this model of GC-ECOPD, CDD866 significantly increased hindlimb muscle volume and tended to reduce atrogene expression. These findings warrant further investigation of ActIIB-R blockade as a therapeutic approach to prevent and restore GC-treated ECOPD-associated muscle wasting, which would increase the therapeutic efficacy of GCs during ECOPD. Presentation: Sunday, July 13, 2025