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

Victor Aguilar1, Samira Alliouachene, Athanassia Sotiropoulos

  • 1INSERM, U845, Paris F-75015, France; Université Paris Descartes, UMRS-845, Paris F-75015, France.

Cell Metabolism
|June 7, 2007
PubMed

Insights

Deleting S6 kinase 1 (S6K1) in muscle cells increases energy stress and triggers metabolic adaptations via AMP-activated protein kinase (AMPK). AMPK inhibition restores cell growth, revealing S6K1

Area of Science:

  • Cellular Metabolism
  • Molecular Biology
  • Muscle Physiology

Background:

  • S6 kinase (S6K) deletion in metazoans leads to small cell size, insulin hypersensitivity, and metabolic adaptations.
  • The precise molecular mechanisms underlying these S6K deletion phenotypes remain largely unelucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms by which S6K deletion impacts cellular energy status and metabolism in skeletal muscle.
  • To determine the role of S6K1 versus S6K2 in mediating these metabolic adaptations and cellular phenotypes.

Main Methods:

  • Analysis of cellular energy metabolites (ATP, phosphocreatine, AMP, inorganic phosphate) in S6K-deficient skeletal muscle cells.
  • Assessment of AMP-activated protein kinase (AMPK) activity and its downstream targets, including mitochondrial biogenesis and fatty acid beta-oxidation.
  • Pharmacological inhibition of AMPK to evaluate its role in S6K-deficient cell phenotypes.

Main Results:

  • S6K-deficient skeletal muscle cells exhibit elevated AMP and inorganic phosphate, coupled with reduced ATP and phosphocreatine, leading to AMPK upregulation.
  • S6K1 deletion specifically induces energy stress and muscle cell atrophy, independent of S6K2.
  • AMPK-dependent mitochondrial biogenesis and fatty acid beta-oxidation are upregulated, depleting lipid content while sparing glycogen.
  • AMPK inhibition in S6K-deficient cells rescues cell growth and nutrient sensitivity.

Conclusions:

  • S6K1 plays a critical role in regulating cellular energy homeostasis and orchestrating the AMPK-dependent metabolic program in skeletal muscle.
  • These findings provide a molecular mechanism linking S6K1 activity to cell mass accumulation, particularly under conditions of a high-calorie diet.
  • Targeting the S6K1-AMPK axis may offer therapeutic strategies for metabolic disorders associated with altered nutrient sensing and energy balance.

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