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Dual regulation of the AMP‐activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle
Author(s) -
Ponticos Markella,
Lu Qi Long,
Morgan Jennifer E.,
Hardie D.Grahame,
Partridge Terence A.,
Carling David
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.6.1688
Subject(s) - phosphocreatine , ampk , amp activated protein kinase , biology , creatine , protein kinase a , skeletal muscle , creatine kinase , adenosine triphosphate , microbiology and biotechnology , biochemistry , kinase , endocrinology , energy metabolism
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.