Article Text

PDF
Insulin-Like Growth Factor I-Mediated Skeletal Muscle Hypertrophy Is Characterized by Increased mTOR-p70S6K Signaling without Increased Akt Phosphorylation
  1. Yao-Hua Song,
  2. Michael Godard,
  3. Yangxin Li,
  4. Scott R. Richmond,
  5. Nadia Rosenthal,
  6. Patrick Delafontaine
  1. This study was supported by National Heart, Lung, and Blood Institute grant 70241 (to P.D.).
  1. Address correspondence to: Dr. Patrick Delafontaine, Department of Medicine, Section of Cardiology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-48, New Orleans, LA 70112-2699; e-mail: pdelafon{at}tulane.edu.
  2. From the Department of Medicine (Y.-H. S., Y.L., P.D.), Section of Cardiology, Tulane University School of Medicine, New Orleans, LA; Department of Health, Sport and Exercise Sciences (M.G., S.R.R.), University of Kansas, Lawrence, KS; Mouse Biology Program (N.R.), European Molecular Biology Laboratory, Rome, Italy.

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/mIgf-I) and wild-type littermates.

Results In the hypertrophic muscle of MLC/mIgf-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.

Key Words
  • insulin-like growth factor I
  • muscle
  • hypertrophy

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.