Transcriptomic Analysis of Peripheral Artery Disease Patient Derived Myotubes Reveals Broad Gene Expression Changes and Alternative Splicing

Abstract

Peripheral Artery Disease (PAD) is a disease characterized by atherosclerosis of the arteries suppling blood to the lower extremities. One of the clinical manifestations of PAD is myopathy of the affected muscles. In order to elucidate the role of gene expression changes in myotubes and their effect on PAD myopathy, we isolated myotubes from PAD and control patients to perform transcriptomic analysis. We hypothesized that myogenic and muscle contractility related gene expression levels change during PAD. Our analysis revealed 690 significant differentially expressed genes. Gene ontology analysis showed significant increase in genes relating to myogenesis and muscle contraction. Hypoxia and mitochondria related genes were also dysregulated in PAD myotubes. Kegg pathway analysis showed genes enriched in muscle contraction pathways as well as adrenergic signaling. Alternative splicing analysis showed 209 genes with differential transcript isoform expression. Gene ontology showed that these genes relate to cell adhesion, apoptosis and autophagy. qPCR and Protein expression analysis confirms some of these transcriptional changes. This study shows the need for further exploration into how transcriptional changes affect the development of myopathies and the progression of PAD. It also shows the ability for isolation patient myotubes as a model for the study of myopathies in PAD.