Impaired intracellular energetic communication in muscles from creatine kinase and adenylate kinase (M-CK/AK1) double knock-out mice.
Previously we demonstrated that efficient coupling between cellular sites of ATP production and ATP utilization, required for optimal muscle performance, is mainly mediated by the combined activities of creatine kinase (CK)- and adenylate kinase (AK)-catalyzed phosphotransfer reactions. Herein, we show that simultaneous disruption of the genes for the cytosolic M-CK- and AK1 isoenzymes compromises intracellular energetic communication and severely reduces the cellular capability to maintain total ATP turnover under muscle functional load. M-CK/AK1 (MAK=/=) mutant skeletal muscle displayed aberrant ATP/ADP, ADP/AMP and ATP/GTP ratios, reduced intracellular phosphotransfer communication, and increased ATP supply capacity as assessed by 18O labeling of [Pi] and [ATP]. An analysis of actomyosin complexes in vitro demonstrated that one of the consequences of M-CK and AK1 deficiency is hampered phosphoryl delivery to the actomyosin ATPase, resulting in a loss of contractile performance. These results suggest that MAK=/= muscles are energetically less efficient than wild-type muscles, but an apparent compensatory redistribution of high-energy phosphoryl flux through glycolytic and guanylate phosphotransfer pathways limited the overall energetic deficit. Thus, this study suggests a coordinated network of complementary enzymatic pathways that serve in the maintenance of energetic homeostasis and physiological efficiency.
Department of Cell Biology, University Medical Center, University of Nijmegen, The Netherlands.
Edwin
E
Janssen
Andre
A
Terzic
Bé
B
Wieringa
Petras P
PP
Dzeja
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002450:Cell Communication / Q000502:physiology; D003402:Creatine Kinase / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology; D006153:Guanosine Diphosphate / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000201:enzymology*; D012146:Rest / Q000502:physiology
D007527:Isoenzymes; D006153:Guanosine Diphosphate; D000244:Adenosine Diphosphate; D006157:Guanosine Monophosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D000263:Adenylate Kinase; C110939:adenylate kinase 1