Subcellular creatine kinase alterations - Implications in heart failure

We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alter ations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myo filaments, sarcoplasmic:reticulum (SR), mitochondrial functions, and CK com partmentation were studied: in situ using selective membrane permeabilizati on of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven-months after surgery, animals w ere in CHF. A decrease in total CK activity could be accounted for by a 4-f old decrease in activity and content (Western blots) of mitochondrial CK an d a 30% decrease in M isoform of CK (MM-K) activity. In myofibrils, maximal force,crossbridge kinetics, and alpha-myosin heavy;chain expression decrea sed, whereas calcium sensitivity of tension development remained-unaltered Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR wer e estimated from the surface of caffeine-induced tension transient (S-Ca) a fter loading with different substrates. In CHF, S-Ca decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxi dative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of res piration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may:Contribute to alterations of energy fluxes and calcium homeostasis in CHF.