Skeletal Muscle Gene Expression Signatures of Obese High and Low Responders to Endurance Exercise Training

Context: Exercise training is known to improve glucose tolerance and reverse insulin resistance in people with obesity. However, some individuals fail to improve or even decline in their clinical traits following exercise intervention. Objective: This study focused on gene expression and DNA methylation signatures in skeletal muscle of low (LRE) and high responders (RES) to 8 weeks of supervised endurance training. Methods: We performed skeletal muscle gene expression and DNA methylation analyses in LRE and RES before and after exercise intervention. Additionally, we applied the least absolute shrinkage and selection operator (LASSO) approach to identify predictive marker genes of exercise outcome. Results: We show that the two groups differ markedly already before the intervention. RES were characterized by lower expression of genes involved in DNA replication and repair, and higher expression of extracellular matrix (ECM) components. The LASSO approach identified several novel candidates (eg, ZCWPW2, FOXRED1, STK40) that have not been previously described in the context of obesity and exercise response. Following the intervention, LRE reacted with expression changes of genes related to inflammation and apoptosis, RES with genes related to mitochondrial function. LRE exhibited significantly higher expression of ECM components compared to RES, suggesting improper remodeling and potential negative effects on insulin sensitivity. Between 45% and 70% of differences in gene expression could be linked to differences in DNA methylation. Conclusion: Together, our data offer an insight into molecular mechanisms underlying differences in response to exercise and provide potential novel markers for the success of intervention.