Glucocorticoid-induced CREB activation and myostatin expression in C2C12 myotubes involves phosphodiesterase-3/4 signaling.
Muscle atrophy in metabolic conditions like chronic kidney disease (CKD) and diabetes are associated with glucocorticoid production, dysfunctional insulin/Akt/FoxO3 signaling and increased myostatin expression. We recently found that CREB, a transcription factor proposed to regulate myostatin expression, is highly phosphorylated in some wasting conditions. Based on a novel Akt-PDE3/4 signaling paradigm, we hypothesized that reduced Akt signaling contributes to CREB activation and myostatin expression. C2C12 myotubes were incubated with dexamethasone (Dex), an atrophy-inducing synthetic glucocorticoid. Akt/CREB signaling and myostatin expression were evaluated by immunoblot and qPCR analyses. Inhibitors of Akt, phosphodiesterase (PDE)-3/4, and protein kinase A (PKA) signaling were used to test our hypothesis. Incubating myotubes with Dex for 3-24 h inhibited Akt phosphorylation and enhanced CREB phosphorylation as well as myostatin mRNA and protein. Inhibition of PI3K/Akt signaling with LY294002 similarly increased CREB phosphorylation. Isobutyl-methylxanthine (IBMX, a pan PDE inhibitor), milrinone (PDE3 inhibitor) and rolipram (PDE4 inhibitor) augmented CREB phosphorylation and myostatin expression. Inhibition of protein kinase A by PKI reverted Dex- or IBMX-induced CREB phosphorylation and myostatin expression. Our study provides evidence supporting a newly identified mechanism by which a glucocorticoid-related reduction in Akt signaling contributes to myostatin expression via CREB activation.
['Xie|Yang|Y|', 'Perry|Ben D|BD|', 'Espinoza|Daniel|D|', 'Zhang|Peng|P|', 'Price|S Russ|SR|']
D000818:Animals D002478:Cells, Cultured D017362:Cyclic AMP Response Element-Binding Protein D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 D005938:Glucocorticoids D051379:Mice D018485:Muscle Fibers, Skeletal D055435:Myostatin D010766:Phosphorylation D051057:Proto-Oncogene Proteins c-akt D015398:Signal Transduction
CREB Myostatin Glucocorticoid Gene expression regulation Insulin resistance Skeletal muscle