Abstract Rationale Skeletal muscle wasting (i.e. cachexia) is a debilitating systemic manifestation of COPD. Muscle transcriptomics can reveal disease-associated pathways and targets beyond clinical biomarkers advancing understanding of the etiology of COPD-cachexia. However, translation of findings remains limited by establishment of human model systems for investigating potential therapeutics to reverse or inhibit COPD-cachexia. Our goal was to test whether COPD-cachexia associated transcriptional dysregulation signatures in bulk skeletal muscle biopsies are preserved in transcriptomics signatures of derived myoblasts, myocytes, and myotubes. Methods Vastus lateralis biopsies were collected from 13 (6M / 7F, 64 ± 9 years) participants including non- COPD (n = 6), and COPD cachexia (n = 3), and controls (n = 9). Cachexia was defined using Evan’s cachexia criteria, composite measure of weight loss coupled with reduced muscle strength, fatigue, anorexia, low muscle mass and/or inflammation, in COPD. Skeletal muscle progenitor cells were isolated from biopsies and differentiated into myoblasts, myocytes, and myotubes and used to generate RNAseq data. Differential gene expression analysis was performed to identify transcripts dysregulated in bulk primary skeletal muscle samples. Weighted gene co-expression network analysis (WGCNA) was used to test whether co-expressed modules of genes in bulk samples were preserved in differentiated cells. Moderate module preservation was characterized as preservation statistic (Z) greater than 2. Modules preserved between bulk and differentiated cells were assessed for correlation to clinical traits using Pearson correlation. Gene set enrichment analysis (GSEA) was performed on genes in preserved modules. Results A total of 632 genes were significantly differentially expressed in bulk samples of COPD participants with compared to without cachexia (Figure 1). WGCNA generated nine co-expressed modules in transcriptomics data from bulk samples. Modules 1, 4, 5, and 9 were significantly correlated with cachexia, module 5 being the most significant (r2=-0.7, p-value= 5.0E-03). Modules 1, 2, 7, and 8 were preserved in myoblasts, 2, 7, and 8 in myotubes and 4, 5, 8, and 9 in myocytes. Modules 1, 4, 5, and 9, enriched with genes involved in metabolic and inflammatory remodeling, catabolic stress and atrophy, and chromatin-driven regeneration, were preserved between bulk skeletal muscle, myocytes, and myoblasts and significantly downregulated in participants with COPD-cachexia. Conclusions Modules 1, 4, 5, 9 were preserved and significantly associated with cachexia indicating myoblasts and myocytes recapitulate mature skeletal muscle networks dysregulated in COPD-cachexia. This provides a foundation for further investigation into degeneration and repair pathway dysregulation in COPD-cachexia using a myocyte-myoblast in vitro model. This abstract is funded by: None
Lukusa-Sawalena et al. (Fri,) studied this question.