© 1999 American Heart Association, Inc.
Original Contribution |
Subcellular Creatine Kinase Alterations
Implications in Heart Failure
From Cardiologie Cellulaire et Moléculaire (E.D.S., V.V., P.M., E.M., J.H., R.V.-C.), U-446 INSERM, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France; Unité de Bioénergétique (X.B., B.S.), Centre de Recherches du Service de Santé des Armées, La Tronche, France; and Departments of Pharmacology and Pathological Anatomy (A.M., A.K.), Medical Faculty, Tartu University, Tartu, Estonia.
Correspondence to Renée Ventura-Clapier, Cardiologie Cellulaire et Moléculaire, U-446 INSERM, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France. E-mail renee.ventura{at}cep.u-psud.fr
Abstract—We have tested the
hypothesis that decreased functioning of creatine kinase (CK) at sites
of energy production and utilization may contribute to
alterations in energy fluxes and calcium homeostasis in congestive
heart failure (CHF). Heart failure was induced by aortic banding in
3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR),
mitochondrial functions, and CK compartmentation were studied in situ
using selective membrane permeabilization of left
ventricular fibers with detergents (saponin for
mitochondria and SR and Triton X-100 for myofibrils). Seven months
after surgery, animals were in CHF. A decrease in total CK activity
could be accounted for by a 4-fold decrease in activity and content
(Western blots) of mitochondrial CK and a 30% decrease in M isoform of
CK (MM-CK) activity. In myofibrils, maximal force, crossbridge
kinetics, and 
-myosin heavy-chain expression decreased, whereas
calcium sensitivity of tension development remained unaltered.
Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR
were estimated from the surface of caffeine-induced tension transient
(SCa) after loading with different substrates. In CHF,
SCa decreased by 23%, and phosphocreatine was 2 times less
efficient in enhancing calcium uptake. Oxidative capacities of the
failing myocardium measured as oxygen consumption per gram
of fiber dry weight decreased by 28%. Moreover, the control of
respiration 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.
Key Words: mitochondrial respiration • myofibril • compartmentation • sarcoplasmic reticulum • skinned fiber
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