Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight.

Abstract

Skeletal muscle atrophy is a common condition in aging, diabetes, and in long duration spaceflights due to microgravity. This article investigates multi-modal gene disease and disease drug networks via link prediction algorithms to select drugs for repurposing to treat skeletal muscle atrophy. Key target genes that cause muscle atrophy in the left and right extensor digitorum longus muscle tissue, gastrocnemius, quadriceps, and the left and right soleus muscles are detected using graph theoretic network analysis, by mining the transcriptomic datasets collected from mice flown in spaceflight made available by GeneLab. We identified the top muscle atrophy gene regulators by the Pearson correlation and Bayesian Markov blanket method. The gene disease knowledge graph was constructed using the scalable precision medicine knowledge engine. We computed node embeddings, random walk measures from the networks. Graph convolutional networks, graph neural networks, random forest, and gradient boosting methods were trained using the embeddings, network features for predicting links and ranking top gene-disease associations for skeletal muscle atrophy. Drugs were selected and a disease drug knowledge graph was constructed. Link prediction methods were applied to the disease drug networks to identify top ranked drugs for therapeutic treatment of skeletal muscle atrophy. The graph convolution network performs best in link prediction based on receiver operating characteristic curves and prediction accuracies. The key genes involved in skeletal muscle atrophy are associated with metabolic and neurodegenerative diseases. The drugs selected for repurposing using the graph convolution network method were nutrients, corticosteroids, anti-inflammatory medications, and others related to insulin.