β2 -Adrenoceptor (β2 -AR) signaling decreases the transcriptional activity of forkhead box O (FoxO), but the underlying mechanisms remain incompletely understood. Here, we investigated how β2 -AR signaling regulates the protein abundance of FoxO and its transcriptional activity in skeletal muscle. We observed that stimulation of β2 -AR with its selective agonist, clenbuterol, rapidly decreased FoxO1 mRNA expression, and this was accompanied by a decrease in either FoxO1 protein level or FoxO transcriptional activity. We subsequently observed that miR-374b-5p and miR-7a-1-3p were rapidly upregulated in response to β2 -AR stimulation. Transfection with mimics of either miRNA successfully decreased FoxO1 mRNA. Moreover, because β2 -AR stimulation increased cAMP concentration, pretreatment with an adenylyl cyclase inhibitor canceled out these effects of β2 -AR stimulation. These results suggest that β2 -AR stimulation results in rapid upregulation of miR-374b-5p and miR-7a-1-3p in myotubes, which in turn results in a decrease in FoxO1 mRNA expression via the β2 -AR-cAMP signaling pathway.
Keywords: FoxO; microRNA; skeletal muscle; ubiquitin ligase; β2-adrenoceptor.
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