S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase.
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.
Aguilar
Victor
V
INSERM, U845, Paris F-75015, France; Université Paris Descartes, UMRS-845, Paris F-75015, France.
Alliouachene
Samira
S
Sotiropoulos
Athanassia
A
Sobering
Andrew
A
Athea
Yoni
Y
Djouadi
Fatima
F
Miraux
Sylvain
S
Thiaudière
Eric
E
Foretz
Marc
M
Viollet
Benoit
B
Diolez
Philippe
P
Bastin
Jean
J
Benit
Paule
P
Rustin
Pierre
P
Carling
David
D
Sandri
Marco
M
Ventura-Clapier
Renée
R
Pende
Mario
M
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*
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