Inhibition of Phosphoinositide 3-Kinase/Protein Kinase B Signaling Hampers the Vasopressin-dependent Stimulation of Myogenic Differentiation

Silvia Sorrentino, Alessandra Barbiera, Gabriella Proietti, Gigliola Sica, Sergio Adamo, Bianca Maria Scicchitano

Research output: Contribution to journalArticle

Abstract

Arginine-vasopressin (AVP) promotes muscle differentiation, hypertrophy, and regeneration through the combined activation of the calcineurin and Calcium/Calmodulin-dependent Protein Kinase (CaMK) pathways. The AVP system is impaired in several neuromuscular diseases, suggesting that AVP may act as a physiological factor in skeletal muscle. Since the Phosphoinositide 3-kinases/Protein Kinase B/mammalian Target Of Rapamycin (PI3K/Akt/mTOR) signaling plays a significant role in regulating muscle mass, we evaluated its role in the AVP myogenic effect. In L6 cells AKT1 expression was knocked down, and the AVP-dependent expression of mTOR and Forkhead box O3 (FoxO) was analyzed by Western blotting. The effect of the PI3K inhibitor LY294002 was evaluated by cellular and molecular techniques. Akt knockdown hampered the AVP-dependent mTOR expression while increased the levels of FoxO transcription factor. LY294002 treatment inhibited the AVP-dependent expression of Myocyte Enhancer Factor-2 (MEF2) and myogenin and prevented the nuclear translocation of MEF2. LY294002 also repressed the AVP-dependent nuclear export of histone deacetylase 4 (HDAC4) interfering with the formation of multifactorial complexes on the myogenin promoter. We demonstrate that the PI3K/Akt pathway is essential for the full myogenic effect of AVP and that, by targeting this pathway, one may highlight novel strategies to counteract muscle wasting in aging or neuromuscular disorders.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume20
Issue number17
DOIs
Publication statusPublished - Aug 27 2019

Keywords

  • Animals
  • Cell Differentiation
  • Cell Line
  • Chromones/pharmacology
  • Forkhead Box Protein O3/metabolism
  • Histone Deacetylases/metabolism
  • MEF2 Transcription Factors/metabolism
  • Morpholines/pharmacology
  • Myoblasts/cytology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics
  • Proto-Oncogene Proteins c-akt/metabolism
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases/metabolism
  • Vasopressins/pharmacology

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