Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity

Abstract

Background: Healthy individuals on the lower end of the insulin sensitivity spectrum also have a reduced gene expression response to exercise for specific genes. The goal of this study was to determine the relationship between insulin sensitivity and exercise-induced gene expression in an unbiased, global manner.

Methods and findings: Euglycemic clamps were used to measure insulin sensitivity and muscle biopsies were done at rest and 30 minutes after a single acute exercise bout in 14 healthy participants. Changes in mRNA expression were assessed using microarrays, and miRNA analysis was performed in a subset of 6 of the participants using sequencing techniques. Following exercise, 215 mRNAs were changed at the probe level (Bonferroni-corrected P<0.00000115). Pathway and Gene Ontology analysis showed enrichment in MAP kinase signaling, transcriptional regulation and DNA binding. Changes in several transcription factor mRNAs were correlated with insulin sensitivity, including MYC, r=0.71; SNF1LK, r=0.69; and ATF3, r= 0.61 (5 corrected for false discovery rate). Enrichment in the 5'-UTRs of exercise-responsive genes suggested regulation by common transcription factors, especially EGR1. miRNA species of interest that changed after exercise included miR-378, which is located in an intron of the PPARGC1B gene.

Conclusions: These results indicate that transcription factor gene expression responses to exercise depend highly on insulin sensitivity in healthy people. The overall pattern suggests a coordinated cycle by which exercise and insulin sensitivity regulate gene expression in muscle.

Fig 1. Overall design of the study.

The overall sequence of study days is shown above an expanded view of the acute exercise bout. During the acute exercise bout, subjects exercise for a total of 48 minutes, consisting of 4 sets of exercise, each set consisting of 8 minutes at 70% HR max, 2 minutes at 90% HR max, and 2 minutes of rest. A biopsy of the vastus lateralis muscle was taken at 30 minutes after completing the four sets of exercise. Bx, Biopsy; VO₂, rate of oxygen consumption; HR, Heart Rate.

Fig 2. Relationships among response of genes (at the probe level) to exercise and insulin sensitivity.

Shown are exercise-induced fold changes in expression for the indicated genes plotted against rates of insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. P values displayed for correlations were corrected using the Benjamini Hochberg method.