Myostatin signaling blockade impacts on muscle wasting in a mouse model of glucocorticoid-treated ECOPD

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COPD is often accompanied by muscle wasting. Muscle wasting intensifies during exacerbations of COPD (ECOPD), partially driven by glucocorticoids (GCs) given as standard-of-care treatment. As GC-driven wasting partially relies on myostatin signaling, we hypothesized that blocking its receptor (with CDD866) would attenuate muscle wasting in GC-treated ECOPD. Emphysema (‘COPD’) was induced in male C57BL/6J mice by intratracheal elastase followed by vehicle or LPS instillation to evoke pulmonary inflammation, mimicking ECOPD. Dexamethasone (GC) was injected daily (‘GC-ECOPD’) and CDD866 (CDD, provided by Versanis Bio) once with the first GC dose. µCT scans were made weekly to confirm development of emphysema, and before and 48h after LPS to measure muscle volume (MV). Excised hindlimb muscles were weighed (MW) and used for gene expression analyses. Compared to COPD (-0.1%), Δ body weight (BW) following GC-ECOPD (-6.4%), but not of GC-ECOPD+CDD (-2.6%), was significantly different (p<0.001). ΔBW did not differ between GC-ECOPD and GC-ECOPD+CDD. Final MW was lower in GC-ECOPD vs COPD (-6.7%, p<0.01), but not in GC-ECOPD+CDD (-3.1%). GC-ECOPD MW did not differ from GC-ECOPD+CDD. In line with our hypothesis, preliminary analysis of ΔMV showed retention of MV in GC-ECOPD+CDD vs loss in GC-ECOPD (+0.7% vs -6.6%, p<0.05). Accordingly, atrogene expression tended to be lower in GC-ECOPD+CDD vs GC-ECOPD. In conclusion, CDD866 attenuates muscle loss and atrophy signaling in GC-ECOPD. These findings warrant further investigation of myostatin signaling blockade as an approach to prevent or restore GC-treated ECOPD-associated muscle wasting, thereby increasing the therapeutic efficacy of GCs.

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