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Study Finds Epigenetic Basis for Exercise-Related Shifts in Muscle Gene Expression

NEW YORK (GenomeWeb News) – Exercise alters methylation patterns at the promoters of skeletal muscle genes, coinciding with exercise-related changes to gene expression, according to a study online today in Cell Metabolism.

"Our muscles are really plastic," corresponding author Juleen Zierath, a clinical integrative physiology researcher at Sweden's Karolinska Institute, said in a statement. "[M]uscle adapts to what you do … and this is one of the mechanisms that allows that to happen."

Zierath and collaborators from Denmark, Sweden, and Ireland tracked methylation patterns in the genome before and after exercise in more than a dozen individuals who were typically inactive. The team uncovered a dip in genome-wide methylation after exercise, including methylation decreases at the promoters of muscle genes that are more highly expressed after exercise. Similar changes occurred in isolated mouse muscles following contraction and in muscle cells exposed to caffeine.

"Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle," the study authors wrote, "and suggest that DNA hypomethylation is an early event in contraction-induced gene activation."

Past studies have explored the role of gene expression patterns in skeletal muscle adaptability to exercise and environmental factors, showing that exercise bumps up the expression of genes and proteins participating in mitochondrial function, energy production, and other metabolic processes, the team explained.

"Exercise increases the messenger RNA expression and protein levels of a plethora of genes regulating mitochondrial function and fuel usage," they wrote. "It remains unknown whether DNA methylation controls these genomic responses."

To look more closely at the molecular mechanism behind such changes, the researchers profiled methylation patterns in muscle biopsy samples from 14 normally sedentary individuals before and after exercise.

Among the approaches used to assess methylation status were a luminometric methylation assay focused on CpG islands where cytosine frequently neighbors guanine, methylated DNA immunoprecipitation and methylcytosine capture combined with quantitative PCR, and bisulfite sequencing.

Overall, researchers saw that acute exercise — in this case a stint on a stationary bike — led to decreased methylation in the genome, especially at the promoters of metabolic genes that are known to be more highly expressed after exercise.

And the more intense the exercise, the more pronounced the drop in promoter methylation, the team reported, leading to enhanced expression of messenger RNA at corresponding genes.

Similarly, when they looked at muscle samples isolated from mice, the researchers found that muscle contraction led to decreased promoter methylation and increased expression of the cellular energy-related genes such as PGC-1-alpha, PDK4, and PPAR-delta.

"Acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle," they wrote, "and suggests that DNA hypomethylation is an early event in contraction-induced gene expression."

In muscle cell culture, caffeine, too, led to lower promoter methylation and higher expression of genes implicated in muscle function. The study authors speculated that this may be because the drug produces the same rise in cytoplasmic calcium levels as that seen in muscle cells exerted through exercise.

"Although mechanical stress, neural input, or circulating hormones alter skeletal muscle gene expression after exercise," they added, the caffeine findings indicate that "disturbances in intracellular homeostasis are sufficient to induce DNA methylation remodeling."

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