title: Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control.
abstract: The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under investigation. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1(-/-) myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy.
authors.affiliation: Inserm, Avenir, U584, Université Paris 5, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, Paris, F-75730, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ohanna
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sobering
authors.forename: Thomas
authors.initials: T
authors.lastname: Lapointe
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.forename: Christophe
authors.initials: C
authors.lastname: Praud
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Petroulakis
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kelly
authors.forename: Athanassia
authors.initials: A
authors.lastname: Sotiropoulos
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
mesh_terms: D000818:Animals; D001284:Atrophy; D001835:Body Weight; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D017353:Gene Deletion; D005822:Genetic Vectors; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D009132:Muscles / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014162:Transfection
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D013002:Somatomedins; C059485:matrigel; D049452:Green Fluorescent Proteins; D003094:Collagen; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2