Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components

Ai Luen Wu, Jeong Ho Kim, Chongben Zhang, Terry G. Unterman, Jie Chen

Research output: Contribution to journalArticle

Abstract

The forkhead transcription factor forkhead box protein O1 (FoxO1), a downstream target of phosphatidylinositol 3-kinase/Akt signaling, has been reported to suppress skeletal myocyte differentiation, but the mechanism by which FoxO1 regulates myogenesis is not fully understood. We have previously demonstrated that a nutrient-sensing mammalian target of rapamycin (mTOR) pathway controls the autocrine production of IGF-II and the subsequent phosphatidylinositol 3-kinase/Akt signaling downstream of IGF-II in myogenesis. Here we report a regulatory loop connecting FoxO1 to the mTOR pathway. Inducible activation of a FoxO1 active mutant in the C2C12 mouse myoblasts blocks myogenic differentiation at an early stage and meanwhile leads to proteasome-dependent degradation of a specific subset of components in the mTOR signaling network, including mTOR, raptor, tuberous sclerosis complex 2, and S6 protein kinase 1. This function of FoxO1 requires new protein synthesis, consistent with the idea that a transcriptional target of FoxO1 may be responsible for the degradation of mTOR. We further show that active FoxO1 inhibits IGF-II expression at the transcriptional activation level, through the modulation of mTOR protein levels. Moreover, the addition of exogenous IGF-II fully rescues myocyte differentiation from FoxO inhibition. Taken together, we propose that the mTOR-IGF-II pathway is a major mediator of FoxO's inhibitory function in skeletal myogenesis.

Original languageEnglish (US)
Pages (from-to)1407-1414
Number of pages8
JournalEndocrinology
Volume149
Issue number3
DOIs
StatePublished - Mar 1 2008

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Skeletal Muscle Fibers
Sirolimus
Insulin-Like Growth Factor II
Muscle Development
Phosphatidylinositol 3-Kinase
TOR Serine-Threonine Kinases
Raptors
Ribosomal Protein S6 Kinases
Forkhead Transcription Factors
Myoblasts
Proteasome Endopeptidase Complex
Protein Kinases
Muscle Cells
Transcriptional Activation
Forkhead Box Protein O1
Food
Proteins

ASJC Scopus subject areas

  • Endocrinology

Cite this

Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components. / Wu, Ai Luen; Kim, Jeong Ho; Zhang, Chongben; Unterman, Terry G.; Chen, Jie.

In: Endocrinology, Vol. 149, No. 3, 01.03.2008, p. 1407-1414.

Research output: Contribution to journalArticle

Wu, Ai Luen ; Kim, Jeong Ho ; Zhang, Chongben ; Unterman, Terry G. ; Chen, Jie. / Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components. In: Endocrinology. 2008 ; Vol. 149, No. 3. pp. 1407-1414.
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