TY - JOUR
T1 - S6 Kinase Deletion Suppresses Muscle Growth Adaptations to Nutrient Availability by Activating AMP Kinase
AU - Aguilar, Victor
AU - Alliouachene, Samira
AU - Sotiropoulos, Athanassia
AU - Sobering, Andrew
AU - Athea, Yoni
AU - Djouadi, Fatima
AU - Miraux, Sylvain
AU - Thiaudière, Eric
AU - Foretz, Marc
AU - Viollet, Benoit
AU - Diolez, Philippe
AU - Bastin, Jean
AU - Benit, Paule
AU - Rustin, Pierre
AU - Carling, David
AU - Sandri, Marco
AU - Ventura-Clapier, Renée
AU - Pende, Mario
N1 - Funding Information:
We thank the Novartis Foundation and the G. Thomas laboratory for the use of S6K mutant mice. We are grateful to F. Bouillaud and G. Thomas for reading the manuscript and helpful discussions and to the members of INSERM U845 for support. We thank Frimorfo Inc., Philippe Mateo, and D. Fortin for skillful technical assistance. This work was supported by grants from the INSERM Avenir program (to M.P.), the Fondation de la Recherche Médicale, the Fondation Schlumberger pour l'Education et la Recherche, the Association Française contre les Myopathies (to A. Sotiropoulos and M.P.), the Association Nationale de la Recherche (to B.V. and M.P.), and Telethon (to M.S.). S.A. is a recipient of a stipend from Region Ile-de-France and Association de Recherche sur le Cancer. R.V.-C. is a Centre National de la Recherche Scientifique employee.
PY - 2007/6/6
Y1 - 2007/6/6
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=34249697628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249697628&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2007.05.006
DO - 10.1016/j.cmet.2007.05.006
M3 - Article
C2 - 17550782
AN - SCOPUS:34249697628
SN - 1550-4131
VL - 5
SP - 476
EP - 487
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -