miR-539-5p regulates transcription in the skeletal muscle of diabetic mice by targeting DNA methyltransferase 3b.

Aberrant DNA methylation is associated with diabetes, but the precise regulatory events that control the levels and activity of DNA methyltransferases (DNMTs) is not well understood. Here we show that miR-539-5p targets and regulates its cellular levels. miR-539-5p and show inverse patterns of expression in skeletal muscle of diabetic mice. By binding to the 3' UTR of , miR-539-5p downregulates its levels in C2C12 cells and in human primary skeletal muscle cells. miR-539-5p- interaction regulates transcription by altering methylation at CpG islands within in C2C12 cells. inhibition alone was sufficient to upregulate transcription. antagonism of miR-539-5p in normal mice induced hyperglycemia and hyperinsulinemia and impaired oral glucose tolerance. These mice had elevated and decreased levels in skeletal muscle. db/db mice injected with miR-539-5p mimics showed improved circulatory glucose and cholesterol levels. Oral glucose tolerance improved together with normalization of  levels in skeletal muscle. Our results support a critical role of miR-539-5p and in aberrant skeletal muscle metabolism during diabetes by regulating transcription; modulating the miR-539-5p- axis might have therapeutic potential for addressing altered skeletal muscle physiology during insulin resistance and type 2 diabetes.