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

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

Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle

SummaryDNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene expression. Whole genome methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after acute exercise. Exercise induced a dose-dependent expression of PGC-1α, PDK4, and PPAR-δ, together with a marked hypomethylation on each respective promoter. Similarly, promoter methylation of PGC-1α, PDK4, and PPAR-δ was markedly decreased in mouse soleus muscles 45 min after ex vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and suggest that DNA hypomethylation is an early event in contraction-induced gene activation

Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

The authors are supported by grants from the Novo Nordisk Foundation (NNF14OC0011493, NNF17OC0030088 and NNF14OC0009941), Swedish Diabetes Foundation (DIA2018-357, DIA2018-336), Swedish Research Council (2015-00165, 2018-02389), the Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068), the Stockholm County Council (SLL20150517, SLL20170159), the Swedish Research Council for Sport Science (P2018-0097), and the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD. L.D. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. B.M.G. was supported by a fellowship from the Wenner-Gren Foundation (Sweden). N.J.P. was supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission, 704978, 675610) and grants from the Sigurd och Elsa Goljes Minne and Lars Hiertas Minne Foundations (Sweden). D.J.B. was supported by the ANZ Mason Foundation and Australian Research Council Discovery Program (ARC DP140104165). Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900) (to J.R.Z.). We thank Dr. Nanjiang Shu from National Bioinformatics Infrastructure Sweden (NBIS) for setting up the web-server. We also thank EGI federated cloud for providing the computer resource for hosting the web-server. We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility supported by the Strategic Research Program (SRP) in Diabetes for the usage of the Seahorse flux analyzer. Open access funding provided by Karolinska Institute.Peer reviewedPublisher PD

Kinetics of GLUT4 Trafficking in Rat and Human Skeletal Muscle

OBJECTIVE—In skeletal muscle, insulin stimulates glucose transport activity three- to fourfold, and a large part of this stimulation is associated with a net translocation of GLUT4 from an intracellular compartment to the cell surface. We examined the extent to which insulin or the AMP-activated protein kinase activator AICAR can lead to a stimulation of the exocytosis limb of the GLUT4 translocation pathway and thereby account for the net increase in glucose transport activity. RESEARCH DESIGN AND METHODS—Using a biotinylated photoaffinity label, we tagged endogenous GLUT4 and studied the kinetics of exocytosis of the tagged protein in rat and human skeletal muscle in response to insulin or AICAR. Isolated ep-itrochlearis muscles were obtained from male Wistar rats. Vastus lateralis skeletal muscle strips were prepared from open muscle biopsies obtained from six healthy men (age 39 11 years an

Comparative profiling of skeletal muscle models reveals heterogeneity of transcriptome and metabolism

We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility, supported by the Strategic Research Program (SRP) in Diabetes, for the use of the Seahorse flux analyzer. AUTHOR CONTRIBUTIONS A.M.A. and N.J.P. conceived and designed research; A.M.A., L.S.P., J.A.B.S., B.M.G., M.S., L.D., A.V.C., and N.J.P. performed experiments; A.M.A., L.S.P., J.A.B.S., B.M.G., M.S., L.D., A.V.C., and N.J.P. analyzed data; A.M.A., L.S.P., J.A.B.S., B.M.G., M.S., L.D., A.V.C., A.K., J.R.Z., and N.J.P. interpreted results of experiments; A.M.A. and N.J.P. prepared figures; A.M.A. and N.J.P. drafted manuscript; A.M.A., L.S.P., J.A.B.S., B.M.G., M.S., L.D., A.V.C., A.K., J.R.Z., and N.J.P. edited and revised manuscript; A.M.A., L.S.P., J.A.B.S., B.M.G., M.S., L.D., A.V.C., A.K., J.R.Z., and N.J.P. approved final version of manuscript.Peer reviewedPublisher PD