B109-20 GDF15-GFRAL Signaling Mediates Cachexia in Pulmonary Emphysema

Rationale Growth differentiation factor 15 (GDF15) is a crucial cytokine controllingenergy metabolism. We previously reported that plasma GDF15 concentrationpositively correlated with muscle wasting phenotype in patients with chronicobstructive pulmonary disease (COPD). Methods Plasma GDF15 concentration was assessed in patients with COPD emphysema beforeand after endoscopic lung volume reduction. GDF15-secreting cell population wascharacterized by analyzing single-cell sequencing data. Muscle strength,pulmonary functions, 6 minute walk and body composition were evaluated andanalyzed. GDF15-Spb (lung epithelial-specific GDF15-deficient), and GDNF FamilyReceptor Alpha Like (GFRAL, GDF15 receptor) - mf (muscle/fat-specificGFRAL-deficient) mice were established with elastase-induced emphysema.Adipocytes and myotubes were used for mechanisms exploration based ontranscriptome, proteome, metabolomics and in vitro experiments. The efficacy ofanti-GDF15 therapy (ponsegromab) for pulmonary emphysema related cachexia wasevaluated in murine models. Results Plasma GDF15 concentration negatively correlated with body fat rate, BMI,muscle strength and muscle mass in patients with COPD emphysema. Moreover,GDF15 level decreased after endoscopic lung volume reduction, coinciding withweight and muscle recovery. Based on single-cell transcriptive sequencing,GDF15 significantly increased in lung epithelial cells in patients with COPD.Consistently, we validated in murine models of elastase-induced emphysema. Emphysemamice exhibited weight loss, fat loss and atrophied skeletal muscle. Increasedexpression of GDF15 were detected in lung tissues, with GFRAL upregulated ininguinal white adipose tissues, epididymal white adipose tissues andgastrocnemius. This cachectic phenotype was markedly attenuated in GDF15-Spbmice and GFRAL-mf mice compared to control mice, suggesting GDF15-GFRAL axis isrequired for cachexia development. In vitro, GDF15 repressed adipogenesis andmyogenesis. Mechanistically, GDF15 downregulated taurine metabolism anddownstream PI3K-Akt signaling. In murine models, administration of ponsegromab,a monoclonal antibody against GDF15, could significantly alleviated emphysema-relatedcachexia. Conclusion GDF15-GFRAL signaling is a critical link between emphysemaand cachexia. GDF15 is a promising therapeutic target for cachexia induced by pulmonaryemphysema This abstract is funded by: None