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. 2017 Nov 9;7(1):15134.
doi: 10.1038/s41598-017-15420-7.

Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans

R C Laker  1 , C Garde  1 , D M Camera  2 , W J Smiles  2 , J R Zierath  1   3 , J A Hawley  2   4 , R Barrès  5
Affiliations

Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans

R C Laker et al. Sci Rep. .

Erratum in

Abstract

High fat feeding impairs skeletal muscle metabolic flexibility and induces insulin resistance, whereas exercise training exerts positive effects on substrate handling and improves insulin sensitivity. To identify the genomic mechanisms by which exercise ameliorates some of the deleterious effects of high fat feeding, we investigated the transcriptional and epigenetic response of human skeletal muscle to 9 days of a high-fat diet (HFD) alone (Sed-HFD) or in combination with resistance exercise (Ex-HFD), using genome-wide profiling of gene expression and DNA methylation. HFD markedly induced expression of immune and inflammatory genes, which was not attenuated by Ex. Conversely, Ex markedly remodelled expression of genes associated with muscle growth and structure. We detected marked DNA methylation changes following HFD alone and in combination with Ex. Among the genes that showed a significant association between DNA methylation and gene expression changes were PYGM, which was epigenetically regulated in both groups, and ANGPTL4, which was regulated only following Ex. In conclusion, while short-term Ex did not prevent a HFD-induced inflammatory response, it provoked a genomic response that may protect skeletal muscle from atrophy. These epigenetic adaptations provide mechanistic insight into the gene-specific regulation of inflammatory and metabolic processes in human skeletal muscle.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Study design. Subjects underwent body composition and exercise testing at the commencement of the experimental period. After 3 days of dietary control, subjects consumed a high-fat low-carbohydrate diet (HFD) for 9 days. Subjects either remained sedentary (Sed-HFD) or performed resistance exercise (Ex-HFD) on days 4, 7 and 10 of the experimental period. Blood samples were collected on days 3, 5, 8 and 11 and skeletal muscle biopsies were obtained before and after the diet/exercise intervention.
Figure 2
Figure 2
Short-term resistance exercise initiates robust transcriptional regulation compared with HFD alone. (A) Principal component analysis (PCA) of RNA-seq for the major two principal components (PC). The 95% confidence ellipses are shown for each group. Heatmaps (B and C) and volcano plots (D and E) represent differentially expressed genes in skeletal muscle before (Pre) and after (Post) 9 days of HFD (Sed-HFD; B and D) or HFD with 3 bouts of resistance exercise training (Ex-HFD; C and E). FDR < 0.1.
Figure 3
Figure 3
Short-term resistance exercise is associated with large-scale transcriptional remodelling in skeletal muscle in the presence of HFD. Venn diagrams representing the number of genes that were up-regulated (A) and down-regulated (B) in Sed-HFD and Ex-HFD group (excludes CHAC1 gene, which was upregulated in Ex-HFD and downregulated in Sed-HFD). The intersection represents the genes that were regulated following both interventions. Gene ontology analysis of genes that were up-regulated (C) and down-regulated (D) exclusively in the Ex-HFD group. FDR < 0.1 is shown by the dotted line.
Figure 4
Figure 4
HFD induces immune and inflammatory genes associated with systemic inflammation, regardless of physical activity. (A) Scatter plot of 344 differentially expressed gene following 9 days of HFD, with or without resistance exercise (Sed-HFD and Ex-HFD intersection). Gene ontology analysis of the 344 genes that were either up-regulated (B) or down-regulated (C) in both the Sed-HFD and Ex-HFD groups. FDR < 0.1 is shown by the dotted line. Plasma profiles of free fatty acids (FFA; D), interleukin 6 (IL-6; E) and TNF-α (F) throughout the intervention period. #p < 0.002 for the effect of time; $p < 0.02 for the effect of exercise.
Figure 5
Figure 5
Differential DNA methylation following short-term HFD with or without resistance exercise. Venn diagrams representing the number of genes that were differentially methylated and differentially expressed following 9 days of HFD (A) and with concomitant resistance exercise (C). Venn diagram showing the number of differentially methylated genes between Sed-HFD and Ex-HFD groups (B). Genomic context of DMRs detected in the Sed-HFD (D) and Ex-HFD (E) groups. Volcano plots showing directional changes and FDR of DMRs in the Sed-HFD (F) and Ex-HFD (G) groups. DNA methylation level relative to transcription start site (TSS) and gene expression (insert) for the genes PYGM (H) and ANGPTL4 (I).
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