title: S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase.
abstract: S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid beta-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet.
authors.affiliation: INSERM, U845, Paris F-75015, France; Université Paris Descartes, UMRS-845, Paris F-75015, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Aguilar
authors.forename: Samira
authors.initials: S
authors.lastname: Alliouachene
authors.forename: Athanassia
authors.initials: A
authors.lastname: Sotiropoulos
authors.forename: Andrew
authors.initials: A
authors.lastname: Sobering
authors.forename: Yoni
authors.initials: Y
authors.lastname: Athea
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
authors.forename: Sylvain
authors.initials: S
authors.lastname: Miraux
authors.forename: Eric
authors.initials: E
authors.lastname: Thiaudière
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Philippe
authors.initials: P
authors.lastname: Diolez
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
authors.forename: Paule
authors.initials: P
authors.lastname: Benit
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
mesh_terms: D000222:Adaptation, Physiological; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D004789:Enzyme Activation; D005215:Fasting; D017353:Gene Deletion; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism; D015151:Immunoblotting; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology*; D010168:Palmitates / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000502:physiology*
chemical_list: D007004:Hypoglycemic Agents; D010168:Palmitates; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D038601:Ribosomal Protein S6; C485184:enhanced green fluorescent protein; C448579:ribosomal protein S6, mouse; D049452:Green Fluorescent Proteins; D000620:Aminoimidazole Carboxamide; D019869:Phosphatidylinositol 3-Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide