Glycolytic buffering affects cardiac bioenergetic signaling and contractile reserve similar to creatine kinase

Abstract

buffering affects cardiac bioenergetic signaling and contractile reserve similar to creatine kinase. Am J Physiol Heart Circ Physiol 285: H883-H890, 2003. First published April 24, 2003 10.1152/ajpheart.00725.2002 and glycolysis represent important energy-buffering processes in the cardiac myocyte. Although the role of compartmentalized CK in energy transfer has been investigated intensely, similar duties for intracellular glycolysis have not been demonstrated. By measuring the response time of mitochondrial oxygen consumption to dynamic workload jumps (t mito) in isolated rabbit hearts, we studied the effect of inhibiting energetic systems (CK and/or glycolysis) on transcytosolic signal transduction that couples cytosolic ATP hydrolysis to activation of oxidative phosphorylation. Tyrode-perfused hearts were exposed to 15 min of the following: 1) 0.4 mM iodoacetamide (IA; n ϭ 6) to block CK (CK activity Ͻ3% vs. control), 2) 0.3 mM iodoacetic acid (IAA; n ϭ 5) to inhibit glycolysis (GAPDH activity Ͻ3% vs. control), or 3) vehicle (control, n ϭ 7) at 37°C. Pretreatment t mito was similar across groups at 4.3 Ϯ 0.3 s (means Ϯ SE). No change in tmito was observed in control hearts; however, in IAA-and IA-treated hearts, t mito decreased by 15 Ϯ 3% and 40 Ϯ 5%, respectively (P Ͻ 0.05 vs. control), indicating quicker energy supply-demand signaling in the absence of ADP/ATP buffering by CK or glycolysis. The faster response times in IAA and IA groups were independent of the size of the workload jump, and the increase in myocardial oxygen consumption during workload steps was unaffected by CK or glycolysis blockade. Contractile function was compromised by IAA and IA treatment versus control, with contractile reserve (defined as increase in rate-pressure product during a standard heart rate jump) reduced to 80 Ϯ 8% and 80 Ϯ 10% of baseline, respectively (P Ͻ 0.05 vs. control), and significant elevations in end-diastolic pressure, suggesting raised ADP concentration. These results demonstrate that buffering of phosphate metabolites by glycolysis in the cytosol contributes appreciably to slower mitochondrial activation and may enhance contractile efficiency during increased cardiac workloads. Glycolysis may therefore play a role similar to CK in heart muscle. glycolysis; energy transduction; mitochondria; regulation of oxidative phosphorylation THE RELATIONSHIP BETWEEN CONTRACTILE function of the myocardium and myocyte bioenergetics is centered on the generation of ATP by oxidative phosphorylation, anaerobic glycolysis, and the conversion of phosphocreatine by creatine kinase (CK). The role of CK as an energy reserve and transfer system in the heart has been intensively studied (1,27,28,30,40), focusing on the functional significance of the compartmentation of CK isozymes to the mitochondria and myofibrils (39,44) and the regulators of CK flux during conditions of altered ATP synthesis or hydrolysis (22). Moreover, changes have been observed in CK activity and levels of its substrates and products in human patients sufferi...

Post-conditioning Preserves Glycolytic ATP During Early Reperfusion: A survival Mechanism for the Reperfused Heart

“…Indeed, our results showed that the ATP produced during prolonged ischemia contributed to sustain 60 % of control heart function at the end of reperfusion (Figure 4). Certainly, IAA is not a specific glycolytic inhibitor, but several reports indicate that a low concentration of IAA, as the one used here, neither inhibits other enzymes, such hexokinase, phosphofructokinase, pyruvate kinase [25], succinate dehydrogenase [26], nor does it inhibit mitochondrial oxidative capacity from reperfused hearts even at higher doses (e.g., 0.3 mM IAA) [27]. In this sense, we suggested that glycolysis also contributed to maintain the mechanical function at early reperfusion in the post-conditioned hearts, as the protective effect of the maneuver was significant inhibited in hearts in which iodoacetate was administered only during reperfusion.…”

Prior heavy exercise elevates pyruvate dehydrogenase activity and muscle oxygenation and speeds O2uptake kinetics during moderate exercise in older adults

“…In studies utilizing iodoacetamide-induced creatine kinase (CK) inhibition (27,36) and CK knockout mice (25), muscle oxidative phosphorylation was activated more quickly than under control conditions when an active PCr system would normally buffer the increase in ADP. Glancy et al (19) demonstrated that the time constant of O 2 utilization by isolated mitochondrial preparations was related linearly to the total creatine (and PCr content) of the preparation.…”

Anoxic cell core can promote necrotic cell death in cardiomyocytes at physiological extracellular Po2

“…IA affects not only CK-mediated energy flux but also glycolytic ATP production through inhibition of the glycolytic enzyme GAPDH (5,9,10,29). Thirteen percent of cardiomyocytes with 0.5 mM IA in the normal glucose concentration medium developed rigor contracture at 40 min [P Ͻ 0.05 by log-rank test; Fig.…”

“…IA has been used by many investigators to inhibit CK (5,9,10,29) despite its lack of specificity. In fact, previous studies have demonstrated that 0.4 mM IA inhibited 70 -90% of the activity of the glycolytic enzyme GAPDH in the isolated perfused rat heart (9, 10), whereas activities of adenylate kinase (9, 10), hexokinase, and phosphofructokinase (5) were unaffected.…”