Bioinformatics, Computational and Systems Biology
Ali Khalilimeybodi, PhD (he/him/his)
AHA Postdoctoral Fellow
UC San Diego
San Diego, California, United States
Padmini Rangamani, PhD (she/her/hers)
University of California, San Diego, California, United States
Comparing model predictions with experimental data from basic studies on HCM mutations in sarcomeric proteins illustrated 83% model accuracy in predicting changes in signaling species. The HCM in silico transcriptomic predicted by the model exhibited satisfactory accuracy compared with common differentially expressed genes (DEGs) from mouse R403Q-αMyHC (70%) and R92W-TnT (81%) HCM mutations. The enrichment analysis of in silico transcriptomic illustrated the upregulation of genes related to muscle contraction and sarcomere organization as well as the downregulation of genes associated with PI3K/AKT pathway activation and Fatty acid cycling and transport. The iCardio model predicted a significant increase in metabolic functions such as 1) creatine kinase systems, 2) spermidine synthesis, 3) release of glucose from Glycogen, 4) purine metabolism, 5) carbohydrate metabolism, 6) palmitate uptake, and 7) biomass generation. On the other hand, the model predicted a significant decrease in 1) fatty acid metabolism, 2) beta-oxidation of fatty acids, 3) Omega-6 fatty acid metabolism, and oxidation of 4) 13Z-eicosenoic acid, 5) pentadecylic acid, 6) cis-vaccenic acid. These results are consistent with experimental observations of shifting cardiac metabolism from fatty acid oxidation to glycolysis in HCM. The model predicted that in the late stages of hypertrophic cardiomyopathy (HCM), a reduction in ATP levels serves as a compensatory mechanism to mitigate the HCM phenotype. Additionally, as the model predicted, activation of AMPK by metformin leads to a decrease in HCM phenotype, implying potential protective benefits of metformin for HCM patients. The model findings also indicated that combination pharmacotherapies may be more effective in HCM treatment. This study offers a novel framework for exploring the interplay between cardiac signaling and metabolism and assessing the efficacy of pharmacological interventions to develop targeted therapeutic strategies for hypertrophic cardiomyopathy.
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