C97-04 Novel Transcriptomic Markers of Type II Myofibers in COPD and COPD Cachexia Provide New Insight to Skeletal Muscle Fiber Shift

Abstract Rationale Skeletal muscle is critical for performance of day-to-day activities and is comprised of three fiber types (I, IIa, and IIx) that are typically characterized by myosin heavy chain expression. An abnormally high proportion of type II fibers in the vastus lateralis, a muscle in the thigh, is a well-established feature of Chronic Obstructive Pulmonary Disease (COPD) and worsens with increased disease severity. The cause of this increased type II myofiber proportion in the vastus lateralis of people with COPD, and its relationship to cachexia, is unknown. Recent advances in spatial transcriptomics allow muscle fiber clusters or single fibers to be studied. Therefore, we aimed to apply spatial transcriptomics to identify differentially expressed transcripts in type II fibers in people with COPD or COPD cachexia. Methods COPD was defined using post-bronchodilator lung function testing. Spatial transcriptomics data was generated from vastus lateralis biopsies of 15 individuals (n = 6 non-COPD controls, n = 9 COPD). COPD cachexia (n = 5) was characterized using Evans Cachexia Criteria, a composite measure of weight loss coupled with reduced muscle strength, fatigue, anorexia, low muscle mass, and/or inflammation. Digital spatial profiling was performed using Nanostring’s GeoMx Human Whole Transcriptome Atlas probe panel and morphology markers SYTO13, Laminin, MYH7, and MYH2. Regions of interest were selected based on tissue morphology and automatic segmentation. RNA-sequencing was performed on an Illumina NextSeq500 and data analyzed using R. Differential expression of type II fibers was assessed in COPD vs controls and cachectic vs non-cachectic COPD. Gene-set enrichment analysis was performed using FUMA and EnrichR. Results A total of 16 significant differentially expressed genes (DEG) (p 0.05, |Log2Fold-Change|0.5) were identified in type II fibers in COPD vs control, and 126 were identified in type II fibers in cachectic versus non-cachectic COPD (Fig.1). Significant DEGs in type II fibers from COPD participants were enriched for gene-sets involved in integrin signaling (upregulated) and regulation of cell cycle/division (downregulated) compared with controls. Significant DEGs in type II fibers from cachectic COPD included genes involved in MAPK signaling (upregulated) and mitochondria function/oxidative phosphorylation (downregulated) compared with non-cachectic COPD. Conclusion We identified novel transcriptomic markers of type II skeletal muscle fibers in participants with COPD and COPD cachexia compared to controls. Many of these genes have not been previously implicated in the fiber type shift or muscle wasting seen in some people with COPD, providing opportunity for new insights. This abstract is funded by: None