Effects of ischemia on skeletal muscle energy metabolism in mice lacking creatine kinase monitored byin vivo31P nuclear magnetic resonance spectroscopy

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Abstract
The aim of this study was to provide in vivo experimental evidence for the proposed biological significance of the creatine kinase (CK)/phosphocreatine (PCr) system in the energy metabolism of skeletal muscle. As a test system we compared hindlimb muscle of knockout mice lacking the cytosolic M‐type (M‐CK−/−), the mitochondrial ScMit‐type (ScCKmit−/−), or both creatine kinase isoenzymes (CK−/−), and in vivo 31P‐NMR was used to monitor metabolic responses during and after an ischemic period. Although single mutants show some subtle specific abnormalities, in general their metabolic responses appear similar to wild type, in contrast to CK−/− double mutants. This implies that presence of one CK isoform is both necessary and sufficient for the system to be functional in meeting ischemic stress conditions. The global ATP buffering role of the CK/PCr system became apparent in a 30% decline of ATP in the CK−/− mice during ischemia. Both M‐CK−/− and CK−/− showed increased phosphomonoester levels during ischemia, most likely reflecting adaptation to a more efficient utilization of glycogenolysis. While in M‐CK−/− muscle PCr can still be hydrolyzed to provide Pi for this process, in CK−/− muscle only Pi from ATP breakdown is available and Pi levels increase much more slowly. The experiments also revealed that the system plays a role in maintaining pH levels; the CK−/− mice showed a faster and more pronounced acidification (pH = 6.6) than muscles of wild type and single knockout mutants (pH = 6.9). Copyright © 1999 John Wiley & Sons, Ltd. Abbreviations used: CK creatine kinase; M‐CK muscle specific cytosolic isoform of creatine kinase; ScCKmit−/− sarcomeric mitochondrial isoform of creatine kinase; M‐CK−/− mice lacking muscle‐specific cytosolic isoform of creatine kinase; ScCKmit mice lacking sarcomeric mitochondrial isoform of creatine kinase; CK−/− mice lacking muscle specific cytosolic and mitochondrial sarcomeric isoform of creatine kinase; AK adenylate kinase