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 (S Ca ) after loading with different substrates. In CHF, S Ca 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. (Circ Res. 1999;85:68-76.)Key Words: mitochondrial respiration Ⅲ myofibril Ⅲ compartmentation Ⅲ sarcoplasmic reticulum Ⅲ skinned fiber T he mechanisms underlying the decline in cardiac pump function in heart failure are incompletely understood. They lead to a gradual increase in left ventricular (LV) end diastolic pressure and a decrease in systolic pressure. In the past decade attention has been focused on the alterations of the various steps in excitation-contraction coupling and intracellular calcium homeostasis, 1-3 whereas the possible involvement of a mismatch in energy supply and demand has received less attention. 4 -6 It has been shown recently that in human heart failure, there is a generalized alteration of the creatine kinase (CK) system with a decrease in total enzyme activity and velocity and alteration in the isoenzyme pattern, which could contribute to the pathogenesis of heart failure. 5 Moreover, in patients with dilated cardiomyopathy, the phosphocreatine (PCr)/ATP ratio, governed by CK activity, may be a predictor of both total and cardiovascular mortality. 7 However, the precise cellular mechanisms by which altered CK may compromise energy fluxes and contractility are not well understood.CK is an important enzyme involved in energy maintenance and energy transfer in muscle and brain cells. It catalyzes the reversible transfer of a phosphate moiety between ATP and creatine. Four d...

Background-Congestive heart failure (CHF) induces abnormalities in skeletal muscle that are thought to in part explain exercise intolerance. The aim of the present study was to determine whether these changes actually result in contractile or metabolic functional alterations and whether they are muscle type specific. Methods and Results-With a rat model of CHF (induced by aortic banding), we studied mitochondrial function, mechanical properties, and creatine kinase (CK) compartmentation in situ in permeabilized fibers from soleus (SOL), an oxidative slow-twitch muscle, and white gastrocnemius (GAS), a glycolytic fast-twitch muscle. Animals were studied 7 months after surgery, and CHF was documented on the basis of anatomic data. Alterations in skeletal muscle phenotype were documented with an increased proportion of fast-type fiber and fast myosin heavy chain, decreased capillary-to-fiber ratio, and decreased citrate synthase activity. Despite a slow-to-fast phenotype transition in SOL, no change was observed in contractile capacity or calcium sensitivity. However, muscles from CHF rats exhibited a dramatic decrease in oxidative capacities (oxygen consumption per gram of fiber dry weight) of 35% for SOL and 45% for GAS (PϽ0.001). Moreover, the regulation of respiration with ADP and mitochondrial CK and adenylate kinase was impaired in CHF SOL. Mitochondrial CK activity and content (Western blots) were dramatically decreased in both muscles. Conclusions-CHF results in alterations in both mitochondrial function and phosphotransfer systems but unchanged myofibrillar function in skeletal muscles, which suggests a myopathy of metabolic origin in CHF. (Circulation.