Image credit: Sasin Tipchai.
Some sections of our DNA are genes, which are instructions for building proteins, while other sections — called enhancers — regulate which genes are switched on or off, when, and in which tissue. New research from the University of Copenhagen and the Karolinska Institutet provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans.
“Regular physical activity decreases the risk of multiple common disorders such as cardiovascular disease, type 2 diabetes, cancer, and neurological conditions, along with the overall risk of mortality,” said Professor Romain Barrès from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and colleagues.
“The beneficial effects of exercise training on human health are partially driven by adaptations of the skeletal muscle tissue.”
“Exercise-induced adaptations include coordinated changes in the expression of genes controlling substrate usage and metabolic efficiency in skeletal muscle.”
“In addition to the adaptations that occur within skeletal muscle cells, exercise exerts systemic effects on whole-body homeostasis by triggering the release of soluble factors from the muscle that signal to distal tissues, such as brain, liver, and adipose tissue.”
“The mechanisms by which training-induced adaptations of skeletal muscle orchestrate positive effects at the whole-body level are poorly understood.”
“We hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle and that this remodeling contributes to the beneficial effects of exercise on human health.”
For the study, the researchers recruited eight healthy Caucasian men (mean age 23 years) and put them through a six-week endurance exercise program.
They collected a biopsy of their thigh muscle before and after the exercise intervention and examined if changes in the epigenetic signature of their DNA occurred after training.
They discovered that after completing the endurance training program, the structure of many enhancers in the skeletal muscle of the young men had been altered.
By connecting the enhancers to genetic databases, the scientists found that many of the regulated enhancers have already been identified as hotspots of genetic variation between individuals.
“Our findings provide a mechanism for the known beneficial effects of exercise,” Professor Barrès said.
“By connecting each enhancer with a gene, we further provide a list of direct targets that could mediate this effect.”
The authors speculate that the beneficial effects of exercise on organs distant from muscle, like the brain, may largely be mediated by regulating the secretion of muscle factors.
In particular, they found that exercise remodels enhancer activity in skeletal muscle that are linked to cognitive abilities, which opens for the identification of exercise training-induced secreted muscle factors targeting the brain.
“Our data provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans,” said Dr. Kristine Williams, also from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen.
The findings are published in the journal Molecular Metabolism.
Kristine Williams et al. Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in the whole-body function and human health. Molecular Metabolism, published online July 10, 2021; doi: 10.1016/j.molmet.2021.101290