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-consum ing biosynthetic pathways, thereby conserving cellular ATP. The creati ne kinase-phosphocreatine system plays a key role in the control of AT P levels in tissues that have a high and rapidly fluctuating energy re quirement. In this study, we provide direct evidence that these two en ergy-regulating systems are linked in skeletal muscle. We show that th e AMPK inhibits creatine kinase by phosphorylation in vitro and in dif ferentiated muscle cells. AMPK is itself regulated by a novel mechanis m involving phosphocreatine, creatine and pH. Our findings provide an explanation for the high expression, yet apparently low activity, of A MPK in skeletal muscle, and reveal a potential mechanism for the co-or dinated regulation of energy metabolism in this tissue. Previous evide nce suggests that AMPK activates fatty acid oxidation, which provides a source of ATP, following continued muscle contraction. The novel reg ulation of AMPK described here provides a mechanism by which energy su pply can meet energy demand following the utilization of the immediate energy reserve provided by the creatine kinase-phosphocreatine system .