Role of creatine kinase in cardiac excitation-contraction coupling: studies in creatine kinase-deficient mice.
To understand the role of creatine kinase (CK) in cardiac excitation-contraction coupling, CK-deficient mice (CK-/-) were studied in vitro and in vivo. In skinned fibers, the kinetics of caffeine-induced release of Ca2+ was markedly slowed in CK-/- mice with a partial restoration when glycolytic substrates were added. These abnormalities were almost compensated for at the cellular level: the responses of Ca2+ transient and cell shortening to an increased pacing rate from 1 Hz to 4 Hz were normal with a normal post-rest potentiation of shortening. However, the post-rest potentiation of the Ca2+ transient was absent and the cellular contractile response to isoprenaline was decreased in CK-/- mice. In vivo, echocardiographically determined cardiac function was normal at rest but the response to isoprenaline was blunted in CK-/- mice. Previously described compensatory pathways (glycolytic pathway and closer sarcoplasmic reticulum-mitochondria interactions) allow a quasi-normal SR function in isolated cells and a normal basal in vivo ventricular function, but are not sufficient to cope with a large and rapid increase in energy demand produced by beta-adrenergic stimulation. This shows the specific role of CK in excitation-contraction coupling in cardiac muscle that cannot be compensated for by other pathways.
Crozatier
Bertrand
B
Unité INSERM U 400, Créteil, France. crozatier@im3.inserm.fr
Badoual
Thierry
T
Boehm
Ernest
E
Ennezat
Pierre-Vladimir
PV
Guenoun
Thierry
T
Su
Jinbo
J
Veksler
Vladimir
V
Hittinger
Luc
L
Ventura-Clapier
Renée
R
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000235:genetics* / Q000502:physiology*; D046508:Culture Techniques; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D016276:Ventricular Function / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D002110:Caffeine; D003402:Creatine Kinase; D007545:Isoproterenol; D002118:Calcium