S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase

Cell Metab. 2007 Jun;5(6):476-87. doi: 10.1016/j.cmet.2007.05.006.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Adenylate Kinase / antagonists & inhibitors
  • Adenylate Kinase / genetics
  • Adenylate Kinase / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / metabolism
  • Animals
  • Cells, Cultured
  • Energy Metabolism
  • Enzyme Activation
  • Fasting
  • Gene Deletion*
  • Glucose Tolerance Test
  • Green Fluorescent Proteins / metabolism
  • Hypoglycemic Agents / metabolism
  • Immunoblotting
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Knockout
  • Muscle Fibers, Skeletal / physiology
  • Muscle, Skeletal / physiology*
  • Palmitates / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleotides / metabolism
  • Ribosomal Protein S6 / physiology*


  • Hypoglycemic Agents
  • Palmitates
  • RNA, Small Interfering
  • Ribonucleotides
  • Ribosomal Protein S6
  • enhanced green fluorescent protein
  • ribosomal protein S6, mouse
  • Green Fluorescent Proteins
  • Aminoimidazole Carboxamide
  • Phosphatidylinositol 3-Kinases
  • Adenylate Kinase
  • AICA ribonucleotide