Impaired muscular contractile performance and adenine nucleotide handling in creatine kinase-deficient mice

Abstract

Creatine kinase (CK) forms a small family of isoenzymes playing an important role in maintaining the concentration of ATP and ADP in muscle cells. To delineate the impact of a lack of CK activity, we studied contractile performance during a single maximal tetanic contraction and during 12 repeated tetanic contractions of intact dorsal flexors of CK knockout (CK−/−) mice. To investigate the effect on ATP regeneration, muscular high-energy phosphate content was determined at rest, immediately after the contraction series, and after a 60-s recovery period. Maximal torque of the dorsal flexors was significantly lower in CK−/− mice than in wild-type animals, i.e., 23.7 ± 5.1 and 33.3 ± 6.8 mN · m · g−1 wet wt, respectively. Lower muscle ATP (20.1 ± 1.4 in CK−/− vs. 28.0 ± 2.1 μmol/g dry wt in controls) and higher IMP (1.2 ± 0.5 in CK−/− vs. 0.3 ± 0.1 μmol/g dry wt in controls) levels at the onset of contraction may contribute to the declined contractility in CK−/− mice. In contrast to wild-type muscles, ATP levels could not be maintained during the series of 12 tetanic contractions of dorsal flexors of CK−/− mice and dropped to 15.5 ± 2.4 μmol/g dry wt. The significant increase in tissue IMP (2.4 ± 1.1 μmol/g dry wt) content after the contraction series indicates that ATP regeneration through adenylate kinase was not capable of fully compensating for the lack of CK. ATP regeneration via the adenylate kinase pathway is a likely cause of reduced basal adenine nucleotide levels in CK−/− mice.