Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle.
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.
Ponticos
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MRC Molecular Medicine, Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, DuCane Road, London W12 0NN.
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Q L
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Morgan
J E
JE
Hardie
D G
DG
Partridge
T A
TA
Carling
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D
D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002999:Clone Cells; D003401:Creatine / Q000378:metabolism; D003402:Creatine Kinase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000201:enzymology; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000032:analysis / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology*; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000032:analysis / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011817:Rabbits; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D012263:Ribonucleosides; D010725:Phosphocreatine; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D003402:Creatine Kinase; D003401:Creatine