Insulin and glucose alter death-associated protein kinase 3 (DAPK3) DNA methylation in human skeletal muscle. Homo sapiens

DNA methylation marks are altered by environmental factors. We tested the hypothesis that DNA methylation is altered in skeletal muscle in response to either insulin or glucose exposure. We performed a genome-wide DNA methylation analysis in skeletal muscle from healthy men before and after insulin exposure. DNA methylation of selected genes was determined in skeletal muscle from healthy and type 2 diabetic men before and after a glucose tolerance test. Insulin reduced DNA methylation in the calcium pump ATP2A3 gene. Insulin increased DNA methylation in the gene body of death-associated protein kinase 3 (DAPK3), a gene involved in cell proliferation, apoptosis and autophagy. DAPK3 methylation was reduced in type 2 diabetic patients. Carbohydrate ingestion reduced DAPK3 DNA methylation in healthy and type 2 diabetic men, suggesting glucose may play a role. In support of this, DAPK3 DNA methylation was inversely correlated with the glucose concentration 2 hours after an oral glucose test. Insulin and glucose exposure acutely alter the DNA methylation profile of skeletal muscle, supporting recent evidence that DNA methylation constitutes a rapidly and adaptive epigenetic mark. Furthermore, insulin and glucose modulate skeletal muscle DAPK3 DNA methylation in a reciprocal manner suggesting a feedback control on the epigenome. Overall design: Skeletal muscle biopsies from 3 different healthy volunteers incubated in either control buffer (biopsy 1) or buffer+120nM insulin (biopsy 2) for one hour.