Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts

Satoru Sumitani, Kayoko Goya, Joseph R. Testa, Haruhiko Kouhara, Soji Kasayama

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Insulin and IGFs are potent inducers of skeletal muscle differentiation. Although PI3K is known to be involved in skeletal muscle differentiation, its downstream targets in this process are not clearly defined. We investigated the roles of Akt and mammalian target of rapamycin (mTOR) in skeletal muscle differentiation. LY294002, a pharmacological inhibitor of PI3K, and the immunosuppressant rapamycin inhibited insulin-induced differentiation of C2C12 myoblasts. LY294002 and rapamycin suppressed myosin heavy chain expression and myotube formation. Transient reporter assays showed that both inhibitors repress muscle creatine kinase (MCK) and myogenin gene transcription. Heterologous expression of Akt1/PKBα potently suppressed MCK gene transcription without affecting myogenin gene transcription, whereas heterologous expression of Akt2 increased myogenin and MCK gene transcription. Finally, overexpression of myogenin rescued the inhibitory effect of rapamycin on MCK gene transcription, whereas it failed to rescue the inhibitory effect of LY294002 and Akt1. These results suggest that insulin regulates myogenic differentiation chiefly at the level of myogenin gene transcription via PI3K and mTOR. PI3K activity, but not mTOR, may regulate transcriptional activity of myogenin. Our data also suggest that Akt1 and Akt2 play distinct roles in myogenic differentiation.

Original languageEnglish
Pages (from-to)820-828
Number of pages9
JournalEndocrinology
Volume143
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Animals
  • Cell Differentiation/drug effects
  • Cell Line
  • Creatine Kinase/biosynthesis
  • Fluorescent Antibody Technique
  • Gene Expression Regulation/physiology
  • Genes, Reporter/genetics
  • Immunoblotting
  • Insulin/pharmacology
  • Mice
  • Muscle, Skeletal/cytology
  • Myogenin/biosynthesis
  • Myosin Heavy Chains/biosynthesis
  • Phosphatidylinositol 3-Kinases/physiology
  • Plasmids/genetics
  • Potassium Channels/physiology
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Transfection

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