Interactions between p-Akt and Smad3 in injured muscles initiate myogenesis or fibrogenesis

Yanjun Dong, Ronak Lakhia, Sandhya S. Thomas, Yanlan Dong, Xiaonan H. Wang, Kleiton Augusto Santos Silva, Liping Zhang

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine whether impaired IGF signaling initiates muscle fibrosis, we generated IGF-IR+/- heterozygous mice by crossing loxP-floxed IGF-IR (exon 3) mice with MyoD-cre mice. IGF-IR+/- mice were studied because we were unable to obtain homozygous IGF-IR-KO mice. In IGF-IR+/- mice, both growth and expression of myogenic genes (MyoD and myogenin; markers of satellite cell proliferation and differentiation, respectively) were depressed. Likewise, in injured muscles of IGF-IR+/- mice, there was impaired regeneration, depressed expression of MyoD and myogenin, and increased expression of TGF-β1, α-SMA, collagen I, and fibrosis. To uncover mechanisms stimulating fibrosis, we isolated satellite cells from muscles of IGFIR +/- mice and found reduced proliferation and differentiation plus increased TGF-β1 production. In C2C12 myoblasts (a model of satellite cells), IGF-I treatment inhibited TGF-β1-stimulated Smad3 phosphorylation, its nuclear translocation, and expression of fibronectin. Using immunoprecipitation assay, we found an interaction between p-Akt or Akt with Smad3 in wild-type mosuse muscles and in C2C12 myoblasts; importantly, IGF-I increased p-Akt and Smad3 interaction, whereas TGF-β1 decreased it. Therefore, in muscles of IGF-IR+/- mice, the reduction in IGF-IR reduces p-Akt, allowing for dissociation and nuclear translocation of Smad3 to enhance the TGF-β1 signaling pathway, leading to fibrosis. Thus, strategies to improve IGF signaling could prevent fibrosis in catabolic conditions with impaired IGF signaling.

Original languageEnglish (US)
Pages (from-to)E367-E375
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number3
DOIs
StatePublished - Aug 1 2013

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Keywords

  • Fibrosis
  • Insulin-like growth factor i
  • Myogenesis
  • Satellite cells
  • Smad3
  • Transforming growth factor-β1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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