IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients.
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.
Erbay
Ebru
E
Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave., B107, Urbana, IL 61801, USA.
Park
In-Hyun
IH
Nuzzi
Paul D
PD
Schoenherr
Christopher J
CJ
Chen
Jie
J
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
D000596:Amino Acids; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse