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Published 8 December 2003. doi:10.1083/jcb.200307158
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© The Rockefeller University Press, 0021-9525/2003/12/931 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 931-936

Report

IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients



Ebru Erbay, In-Hyun Park, Paul D. Nuzzi, Christopher J. Schoenherr and Jie Chen

Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801

Address correspondence to Jie Chen, Dept. of Cell and Structural Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave., B107, Urbana, IL 61801. Tel./Fax: (217) 265-0674. email: jiechen{at}uiuc.edu

Insulin-like growth factors (IGFs) are essential for skeletal muscle development, regeneration, and hypertrophy. Although autocrine actions of IGF-II are known to initiate myoblast differentiation, the regulatory elements and upstream signaling pathways for myogenic expression of IGF-II remain elusive. Here, we report the regulation of IGF-II transcription by mTOR, as well as by amino acid sufficiency, through the IGF-II promoter 3 and a downstream enhancer during C2C12 myoblast differentiation. Furthermore, we present evidence that IGF production, and not IGF signaling, is the primary target for mTOR's function in the initiation of differentiation. Moreover, myogenic signaling by mTOR is independent of its kinase activity and mediated by the PI3K–Akt pathway. Our findings represent the first identification of a signaling pathway that regulates IGF-II expression in myogenesis and implicate the mTOR–IGF axis as a molecular link between nutritional levels and skeletal muscle development.

Key Words: IGF; rapamycin; skeletal muscle differentiation; PI3K; Akt

Abbreviations used in this paper: 4EBP1, eIF-4E binding protein 1; c.a., constitutively active; IGF, insulin-like growth factor; ME, muscle enhancer; MHC, myosin heavy chain; P3, promoter 3; PI3K, phosphatidylinositol 3-kinase; RPA, RNase protection assay; RR, rapamycin resistant; RR/KI, RR and kinase inactive; S6K1, S6 kinase 1.


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