Insulin-like growth factor I-mediated skeletal muscle hypertrophy is characterized by increased mTOR-p70S6K signaling without increased Akt phosphorylation

J Investig Med. 2005 Apr;53(3):135-42. doi: 10.2310/6650.2005.00309.

Abstract

Background: Insulin-like growth factor I (IGF-I) is an anabolic hormone that is known to induce skeletal muscle hypertrophy. However, the signaling pathways mediating IGF-I's hypertrophic effect in vivo are unknown.

Method: The phosphorylation of 46 proteins was investigated by Kinetworks proteomic analysis in the gastrocnemius muscle of transgenic mice overexpressing IGF-I myosin light chain/muscle specific IGF-I (MLC/mlgf-I) and wild-type littermates.

Results: In the hypertrophic muscle of MLC/mlgf-I mice, we observed increased phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1; 53% increase), the mammalian target of rapamycin (mTOR; 112% increase), and p70 S6 kinase (p70S6K) (254% increase) but no significant change in Akt phosphorylation (4% decrease). Furthermore, we found reduced phosphorylation of MAP kinase kinase 1 and 2 (MEK1/2) (60% decrease) and of mitogen-activated protein kinase kinases 3 and 6 (MKK3/6) (50% decrease) in muscle from transgenic mice, suggesting that the hypertrophic and mitogenic effects of IGF-I are mediated via distinct signaling pathways in skeletal muscle and that inhibition of the mitogen-activated protein (MAP) kinase pathway may be required for the IGF-I-induced hypertrophic effect. Single-fiber analysis revealed a trend toward a higher percentage of the fast twitch fibers (IIb and IIx) in the transgenic mice.

Conclusion: Persistent overexpression of IGF-I in mice skeletal muscle results in hypertrophy, which is likely mediated via the mTOR/p70S6K pathway, potentially via an Akt-independent signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Gene Expression
  • Hypertrophy
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology*
  • Phosphoproteins / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases

Substances

  • Phosphoproteins
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Insulin-Like Growth Factor I
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • mTOR protein, rat
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa