Institution: | 1INSERM, U845, Paris F-75015, France 2Université Paris Descartes, UMRS-845, Paris F-75015, France 3INSERM, U769, Châtenay-Malabry F-92296, France 4Université Paris-Sud, Faculté de Pharmacie, IFR141, Châtenay-Malabry F-92296, France 5CNRS, UPR 9078, Université Paris Descartes, Paris F-75015, France 6CNRS, UMR 5536, Bordeaux F-33076, France 7INSERM, U567, Paris F-75014 8Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014, France 9INSERM, U676, Paris F-75019, France 10Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London W12 0NN, UK 11Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, Padova 35129, Italy |
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 β-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. |