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Glucocorticoid-induced CREB activation and myostatin expression in C2C12 myotubes involves phosphodiesterase-3/4

Yang Xie1, Ben D Perry2, Daniel Espinoza3

  • 1Department of Medicine, Renal Division, Emory University, Atlanta, GA 30322, USA; Department of Nephrology, Xiangya Hospital and Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China; Department of Nephrology, Beijing Hospital, Beijing 100730, PR China.

Biochemical and Biophysical Research Communications
|July 21, 2018
PubMed

Insights

Glucocorticoids reduce Akt signaling, leading to increased CREB phosphorylation and myostatin expression, contributing to muscle atrophy in metabolic diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Muscle atrophy in chronic kidney disease (CKD) and diabetes is linked to glucocorticoids, impaired insulin/Akt/FoxO3 signaling, and elevated myostatin.
  • CREB (cAMP response element-binding protein) phosphorylation is observed in some wasting conditions and is hypothesized to regulate myostatin.

Purpose of the Study:

  • To investigate the hypothesis that reduced Akt signaling contributes to CREB activation and subsequent myostatin expression.
  • To elucidate the role of the Akt-PDE3/4 signaling pathway in glucocorticoid-induced muscle atrophy.

Main Methods:

  • C2C12 myotubes were treated with dexamethasone (Dex) to induce atrophy.
  • Western blotting and qPCR were used to assess Akt/CREB signaling and myostatin expression.
  • Inhibitors of Akt, phosphodiesterase (PDE)-3/4, and protein kinase A (PKA) were employed to test the signaling pathway.

Main Results:

  • Dexamethasone treatment inhibited Akt phosphorylation while increasing CREB phosphorylation and myostatin expression (mRNA and protein).
  • Inhibition of PI3K/Akt signaling mimicked these effects, increasing CREB phosphorylation.
  • Inhibitors of PDE3/4 (milrinone, rolipram) and a pan-PDE inhibitor (IBMX) enhanced CREB phosphorylation and myostatin expression.
  • PKI, an inhibitor of PKA, reversed the Dex- and IBMX-induced increases in CREB phosphorylation and myostatin expression.

Conclusions:

  • Glucocorticoid-induced reduction in Akt signaling activates CREB.
  • Activated CREB leads to increased myostatin expression, a mechanism contributing to muscle atrophy in metabolic conditions.
  • This study identifies a novel Akt-PDE3/4-PKA-CREB signaling axis involved in glucocorticoid-mediated muscle wasting.
Keywords:
CREBGene expression regulationGlucocorticoidInsulin resistanceMyostatinSkeletal muscle

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