Abstract
Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response.
Highlights
Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity
We address this by integrating a traditional genome-wide association study (GWAS) approach with the analysis of skeletal muscle transcriptomics data within HERITAGE, one of the largest studies to evaluate the response of several physiological measurements to EET
We have shown that variation in insulin sensitivity across a normal healthy population and its modulation by EET is a complex trait where combined variation in genes linked to the KEGG pathways cholinergic signalling, calcium signalling, axon guidance and chemokine signalling is likely to be an important component
Summary
Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The molecular mechanisms underlying variation in Si in a healthy population and the heterogeneous ability to improve S i through EET are currently not well understood We address this important question by computational analysis of genome-wide association study (GWAS) and skeletal muscle gene expression datasets derived from the HERITAGE Family Study. Homozygous mouse knockouts of four of these candidates show alterations in glucose disposal and other relevant phenotypes, suggesting that our approach is likely to have identified genes causally linked to S i Analysis of both GWAS and skeletal muscle transcriptomics data shows that a molecular signature linked to calcium-regulated cholinergic signalling may be an important component of the observed variation in Si in a healthy population and predicts exercise-induced changes in S i both in HERITAGE and an independent clinical exercise study
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