Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control.
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.
Ohanna
Mickaël
M
Inserm, Avenir, U584, Université Paris 5, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, Paris, F-75730, France.
Sobering
Andrew K
AK
Lapointe
Thomas
T
Lorenzo
Lazaro
L
Praud
Christophe
C
Petroulakis
Emmanuel
E
Sonenberg
Nahum
N
Kelly
Paul A
PA
Sotiropoulos
Athanassia
A
Pende
Mario
M
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
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