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 expres...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2018-09, Vol.503 (3), p.1409-1414
Main Authors: Xie, Yang, Perry, Ben D., Espinoza, Daniel, Zhang, Peng, Price, S. Russ
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Animals
Cells, Cultured
CREB
Cyclic AMP Response Element-Binding Protein - metabolism
Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
DEXAMETHASONE
Gene expression regulation
Glucocorticoid
Glucocorticoids - pharmacology
INSULIN
Insulin resistance
KIDNEYS
MESSENGER-RNA
Mice
Muscle Fibers, Skeletal - drug effects
Muscle Fibers, Skeletal - metabolism
Myostatin
Myostatin - biosynthesis
Myostatin - metabolism
PHOSPHODIESTERASES
Phosphorylation - drug effects
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - drug effects
Skeletal muscle
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.07.056