Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle

EMBO J. 1998 Mar 16;17(6):1688-99. doi: 10.1093/emboj/17.6.1688.


The AMP-activated protein kinase (AMPK) is activated by a fall in the ATP:AMP ratio within the cell in response to metabolic stresses. Once activated, it phosphorylates and inhibits key enzymes in energy-consuming biosynthetic pathways, thereby conserving cellular ATP. The creatine kinase-phosphocreatine system plays a key role in the control of ATP levels in tissues that have a high and rapidly fluctuating energy requirement. In this study, we provide direct evidence that these two energy-regulating systems are linked in skeletal muscle. We show that the AMPK inhibits creatine kinase by phosphorylation in vitro and in differentiated muscle cells. AMPK is itself regulated by a novel mechanism involving phosphocreatine, creatine and pH. Our findings provide an explanation for the high expression, yet apparently low activity, of AMPK in skeletal muscle, and reveal a potential mechanism for the co-ordinated regulation of energy metabolism in this tissue. Previous evidence suggests that AMPK activates fatty acid oxidation, which provides a source of ATP, following continued muscle contraction. The novel regulation of AMPK described here provides a mechanism by which energy supply can meet energy demand following the utilization of the immediate energy reserve provided by the creatine kinase-phosphocreatine system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Amino Acid Sequence
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Clone Cells
  • Creatine / metabolism
  • Creatine Kinase / analysis
  • Creatine Kinase / antagonists & inhibitors
  • Creatine Kinase / metabolism*
  • Enzyme Inhibitors
  • Hydrogen-Ion Concentration
  • Liver / enzymology
  • Models, Chemical
  • Molecular Sequence Data
  • Multienzyme Complexes / analysis
  • Multienzyme Complexes / metabolism*
  • Muscle Fibers, Skeletal / enzymology
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / enzymology*
  • Phosphocreatine / metabolism
  • Phosphorylation
  • Protein Kinases / analysis
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Rabbits
  • Rats
  • Ribonucleosides / pharmacology


  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Ribonucleosides
  • Phosphocreatine
  • Aminoimidazole Carboxamide
  • acadesine
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Creatine Kinase
  • Creatine