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1Heart Foundation Research Centre, Griffith University, Gold Coast, Queensland 9726, Australia; and 2Laboratory for Physiology and 3Department of Molecular Cell Physiology, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands
Submitted 19 August 2002 ; accepted in final form 21 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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glycolysis; energy transduction; mitochondria; regulation of oxidative phosphorylation
Compared with CK, glycolysis has received little attention as an integral
part of myocyte energy transfer and signaling. Previous studies
(41) have illustrated a degree
of functional compartmentalization of glycolytic metabolism and energy stores
plus the preferential use of glycolytic rather than oxidatively produced ATP
by the sarcolemma. Whereas anaerobic glycolysis may only produce as little as
3–7% of the total ATP under aerobic conditions in ex vivo preparations
(8,
17), its contribution to
cellular bioenergetics may increase significantly during ischemia and hypoxia
(31). In addition, ATP from
glycolysis may be used in the heart early during dynamic workload changes
(7), as observed previously in
skeletal muscle (24). We can
measure the time course of oxygen consumption
(
O2) in response to
pacing-induced workload steps, which reflects the transcytosolic energy
signaling speeds between myofibrils and ion pumps and the mitochondria in
isolated rabbit hearts to match ATP synthesis to hydrolysis
(7,
37,
38). The mitochondrial delay
time (tmito) is sensitive to altered exogenous substrate
(35) and ischemia
(46). Recently, we
(10) observed that inhibition
of CK led to a dose-dependent quickening in tmito combined
with a loss of isovolumic contractile reserve, findings that argued against
obligatory cytosolic energy transfer via CK rather suggesting that CK is an
active ADP/ATP buffer that locally increases the effectiveness of ATP
consuming processes, but thereby effectively slows the signal from the sites
of ATP hydrolysis to oxidative phosphorylation. Similarly, the local
glycolytic buffering near ion pumps and myofibrils might directly enhance
contractile function (41). We
investigate here whether such buffering by glycolysis slows the activation of
oxidative phosphorylation in a similar way as the CK system.
The aim of the present experiments was therefore to test the effect of inhibiting glycolysis alone, or in combination with CK, on contractile function and cytosolic signaling speeds in steady state and during three levels of dynamically increased cardiac workload. This inhibition was achieved by the differential infusion of the sulfhydryl-enzyme blockers iodoacetamide (IA) and iodoacetic acid (IAA), used previously by us (10) and by others (15, 23, 32–34) to preferentially reduce CK and GAPDH activity, respectively. On the basis of our preliminary findings (36), we predicted that the removal of ATP and ADP buffering capacity of glycolysis alone or in combination with CK inhibition would speed up signaling to oxidative phosphorylation at the expense of a compromised ability to perform acute increases in myocardial workload. Such findings, compared with similar data for CK, would define the role of glycolysis in the family of local energy buffering, energy transfer, and signaling systems within the myocyte that determine cardiac function during health and disease.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Hearts were perfused in a constant flow, nonrecirculating Langendorff mode
with Tyrode buffer containing (in mM) 128.3 NaCl, 4.7 KCl, 1.36
CaCl2, 1.05 MgCl2, 20.2 NaHCO3, 0.42
NaH2PO4, 10.0 glucose, and 2.0 pyruvate. The pyruvate
was included to provide substrate to the mitochondria even in the experimental
group with strong inhibition of glycolysis (see DISCUSSION).
Adenosine (10–5 mM) was incorporated in the Tyrode
solution to obtain constant maximal vasodilation and therefore constant
maximal oxygen supply in our preparation. The buffer was maintained at
37°C and continuously gassed with 95% O2-5% CO2,
yielding a pH of 7.4 and a PO2 of 
640 mmHg.
Spontaneous heart rate was lowered from 230 to <120 beats/min by
crushing the atrioventricular node, and hearts were subsequently paced
slightly above this intrinsic rate (132 ± 1 beats/min) via bipolar
electrodes placed on the right ventricular outflow tract. The right atrium was
closed by ligation of the caval veins and venous effluent left the heart by
the cannulated pulmonary artery. The left ventricle was drained of Thebesian
flow with the use of a 22-gauge polyethylene catheter pierced through the
apex.
Isovolumic contractile function was assessed using a latex balloon secured
into the left ventricle with a purse-string suture in the atrial appendage.
The balloon was connected to a pressure transducer (model P23 ID, Gould;
Oxnard, CA) and the end-diastolic pressure was adjusted to 3 mmHg by
increasing balloon volume. Perfusion flow rate was subsequently adjusted to
generate an initial coronary perfusion pressure of 80 mmHg, measured
immediately above the heart with a second pressure transducer, and this flow
was not altered during experiments. Arterial and venous perfusate samples were
continuously drawn through two cuvettes containing custom-made Clark-type
oxygen electrodes (time constant 1.5 s), calibrated before and after the
experiment. All pressure and oxygen tension data were simultaneously displayed
on a chart recorder and digitally stored on a personal computer (Olivetti
Pro). Myocardial O2
(MO2, in
µmol·min–1·g dry
wt–1) was calculated as the product of coronary
flow and the arterial-venous oxygen concentration difference (O2
solubility = 1.34 µmol O2·l
Tyrode–1·mmHg–1).
Calculation of tmito. Detailed description of
the techniques, including the oxygen transport model and the equations,
assumptions, and correction values, is to be found elsewhere
(37,
38). Briefly, the venous mean
response time (tv) is integrated from the time course of
the venous PO2 (PvO2) during a
step to and from a higher heart rate. Previous studies have shown that there
is an initial overshoot in rate-pressure product (RPP) before steady state is
reached, which is accounted for by the RPP response time
(tRPP), and also a small initial increase in
(PvO2) [initial deflection time
(tid)] due to transient increases in venous outflow, and
hence tv is corrected for these parameters. To correct
tv for delays in diffusion and transport of oxygen between
the mitochondria and the oxygen electrode, we subtract the transport time
(ttransport), obtaining the true response time of
O2 at the level of the
mitochondria during a dynamic step in workload: tmito =
tv – ttransport. We therefore
use tmito as an index of intracellular energy
transfer/signaling speed during rapid increases in metabolic demand in our
isovolumic preparation.
ttransport is calculated from the venous O2
response times to a combination of three experimental interventions conducted
in series following the heart rate steps
(37). First, a small step in
arterial concentration (ACS) is made by instantaneous exchange immediately
above the heart of 10% of the normal oxygenated Tyrode with identical Tyrode
gassed with 95% N2-5% CO2 (PO2
30 mmHg at coronary ostia) and the venous O2 response to this
step is assessed. Intravascular transit time is calculated with the use of a
indicator-dilution step with Evans blue bound to albumin (EBS) as the
intravascular indicator, infused immediately above the heart and detected in a
densitometer adjacent to the venous oxygen electrode.
ttransport is derived from the ACS with a numerically
somewhat smaller contribution from the EBS, but a second estimate is
independently obtained from a step in perfusion flow (PFS) made by rapid
extraction of 10% of the normal coronary flow from a side arm in the
aortic cannula. All ACS, EBS, and PFS steps are conducted at both intrinsic
pacing rate (132 beats/min) and the highest test heart rate (220 beats/min) to
assess the effect of heart rate on oxygen transport and to check the
sensitivity of the preparation to small reductions in oxygen supply. These
steps are repeated after the treatment to assess the effects of IAA and IA on
oxygen transport. The technique has been tested and compared with other
techniques such as near-infrared spectroscopy, nuclear magnetic resonance
(NMR) spectroscopy (7), and
heat rate measurements as extensively discussed in a review
(37).
Experimental protocol. All hearts were equilibrated for 30 min
after instrumentation, followed by assessment of baseline hemodynamic
function. During the next 30 min the first series of steps to calculate
tmito was performed (as outlined in Calculation of
tmito) incorporating randomized heart rate steps from
basal heart rate (132 beats/min) to 160, 190, and 220 beats/min and back, plus
the ACS, EBS, and PFS steps at 132 and 220 beats/min. Hearts were then
randomly assigned to one of three treatment groups to receive 0.4 mM IA (IA
treated, n = 6), 0.3 mM IAA (IAA treated, n = 5), or vehicle
(Tyrode buffer) infusion (control hearts, n = 7) over the next 15
min. Concentrations given are final values (in mM) in the perfusing solution
after infusion of stock solutions into a side arm of the aortic cannula at
1.2 ml/min with an infusion pump (Vickers Medical; Hampshire, UK). Hearts
were subsequently allowed 15 min for drug washout and reequilibration before
the second series of tmito steps. Measurements of
contractile function were made before and after IA or IAA infusion.
Contractile reserve was defined as the increase in RPP (heart rate x
left ventricular developed pressure) for a 132–220 beats/min heart rate
step made before and after treatment. At the end of experiments, a piece
(1 g) of left ventricle was rapidly excised into isopentane (precooled in
liquid N2) and immediately freeze dried at –70°C
overnight, before storage at –80°C for biochemical analysis. The
remaining heart was trimmed of extraneous tissue and used for blotted wet and
dry (48 h at 80°C) weight measurements.
Biochemical assays. Tissue samples (5–10 mg) were cut from
the freeze-dried heart sections and homogenized at 4°C for 20 s in 0.1 M
potassium phosphate buffer containing 1 mM EDTA and 1 mM
-mercaptoethanol (pH 7.4). Triton X-100 was added to the homogenate at a
final concentration of 0.1% before measurement of total CK activity coupled to
NADH production at 25°C with the use of an absorbance wavelength of 340 nm
(2). Adenylate kinase (AK) and
GAPDH activities were assayed also at 25°C according to methods described
by Bergmeyer (2). All enzyme
activities are reported as international units (1 IU = µmol/min)/mg of dry
heart weight tissue. All chemical reagents used were of analytical grade and
were obtained from Sigma (St. Louis, MO) or Boehringer Mannheim (Mannheim,
Germany).
The effect of IAA and IA on mitochondrial state 3
O2 after the addition of
1 mM ADP was determined in a respirometer containing isolated rabbit heart
mitochondria with 5 mM pyruvate and 2 mM malate as carbon sources.
Statistical analysis. All data are presented as means ± SE except where indicated otherwise. Comparisons among treatment groups were made using one-way ANOVA with the Newman-Keuls post hoc test used to examine specific differences between group means if ANOVA had reported significance. Measurements made before and after treatment within groups were compared using the Student's paired t-test or ANOVA for repeated measures as necessary. A value of P < 0.05 was considered statistically significant for all comparisons.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Effect of IA and IAA on contractile function. There was no difference in the wet (7.7 ± 0.4 g wet wt) and dry (1.3 ± 0.1 g dry wt) heart weights or in the initial coronary flow rates (12.6 ± 0.4 ml·min–1·g wet wt–1) between the three groups of hearts. Table 2 summarizes the isovolumic contractile indexes measured in hearts from the three treatment groups measured immediately before infusion of the test compound and after the 15-min washout period. As shown, there was no difference in any parameter between groups' pretreatment, but significant systolic and diastolic impairment after inhibition of glycolysis. Systolic left ventricular pressure was significantly decreased in the IAA group, whereas end-diastolic pressure was elevated in both the IA- and IAA-treated hearts, findings consistent with our and others previous use of these compounds (10, 15, 32, 34) and potentially reflecting an increase in the free cytosolic [ADP]. Contractile function stabilized after the washout period and no significant deterioration was observed during the second series of heart rate steps.
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Contractile reserve in our preparation is defined as the relative increase
in RPP during a step in heart rate from 132 to 220 beats/min, measured before
and after treatment. Pretreatment contractile reserve was 3,385 ± 293,
5,243 ± 1,062, and 5,475 ± 702 mmHg/min in control, IAA, and IA
heart groups, respectively (P > 0.05). Contractile reserve was
significantly reduced with the use of IAA (4,092 ± 777 mmHg/min) and IA
(4,239 ± 652 mmHg/min) treatment (80% of pretreatment; P
< 0.05), a finding reported previously for CK inhibition
(10,
34) but not for glycolytic
blockade. Contractile reserve in control hearts was well maintained at
109% of pretreatment values (3,583 ± 172 mmHg/min).
Reduction in contractile reserve was apparently independent of changes in
oxidative metabolism of the hearts: the
MO2 increases during the
132–220 beats/min heart rate step for control, IAA-, and IA-treated
hearts changed nonsignificantly posttreatment at –9.5 ± 2.2%,
–4.7 ± 3.5%, and –7.0 ± 1.5%, respectively.
ttransport, which characterizes oxygen transport, was not
affected by the IA or IAA infusion (see
Table 3). We have previously
shown in mitochondria isolated from 0.4 mM IA-treated hearts that state 3 and
4 O2 stimulated with ADP
is unaffected, suggesting no damage to oxidative phosphorylation in these
hearts (10). State 3
respiration in isolated mitochondria was not affected by addition of up to 1.5
mM IA or up to 1 mM IAA, appreciably higher concentrations than used during
perfusion. These data therefore show that oxidative metabolism and oxygen
transport in the heart is not compromised by the IA and IAA infusion.
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Taken together, the above observations show that contractile function can be effectively maintained at low cardiac workloads without appreciable CK and/or glycolytic activity but the ability of hearts to undergo rapid increases in performance is compromised, reflecting the important role of these energy systems in buffering local ATP levels.
Energy signaling speeds in absence of glycolysis or CK. We
estimate the delay time in ATP hydrolysis-to-synthesis coupling from the time
course of O2 during three
levels of submaximal workload elevations by pacing hearts from baseline (132
beats/min) to 160, 190, and 220 beats/min and back. This index,
tmito, is calculated from the (PvO2)
curve (tv 9–12 s) and corrected for
tRPP (1–3 s), tid
(0.1–0.2 s), and ttransport (4–6 s)
(see METHODS). From Table
3 it can be seen that neither prenor posttreatment
ttransport values differ among groups and there is a
small, similar posttreatment increase in ttransport across
the groups (12%). Table 4
gives the mean pretreatment tv values for control, IAA,
and IA heart groups during heart rate steps from 132 to 160, 190, and 220
beats/min, respectively. tv is calculated during both the
upward and downward heart rate step, but there was no difference (P
> 0.05 data not shown), and thus the average is given. Two-way ANOVA
revealed that there was no pretreatment difference between heart groups at any
heart rate; however, tmito significantly increased in all
groups with increasing heart rate (P < 0.05), with a parallel
prolongation in the tRPP values from 1.3 ± 0.1 s
(160 beats/min) to 2.1 ± 0.2 and 3.0 ± 0.2 s (220 beats/min), a
finding observed previously
(6). tid
did not differ significantly with heart rate either before or after treatment
in any group.
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Posttreatment changes in tmito (see Fig. 1) show that inhibition of glycolysis alone (IAA) or in combination with CK (IA) causes a significant quickening in the response time of ATP synthesis to a step in energy utilization compared with the unchanged tmito values over time in control hearts. The faster tmito in the IAA and IA groups was independent of the size of the workload transition tested, with all heart rate steps being significantly different from pretreatment (P < 0.05; two-way ANOVA). In addition, the change in pre- to posttreatment tmito observed in IA-treated hearts was significantly larger than that in the IAA group. Figure 2 combines the posttreatment values of tmito in the current study to those found in our earlier study (10), in which glucose alone was used as substrate and IA was infused at a range of concentrations (0.1, 0.2, and 0.4 mM; only the latter is shown for clarity). Figure 2 illustrates the accelerating effect of pyruvate addition alone to the buffer on tmito in control hearts. The addition of pyruvate reduces glycolytic activity already substantially (see DISCUSSION) and further blockade of glycolysis with IAA has an additional small, although significant, effect on tmito. The synergistic effect of glycolysis and CK inhibition is such that the IA-treated hearts with both pyruvate and glucose as substrates (present study) have the fastest transcytosolic signaling speeds.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Acute inhibition of CK and GAPDH was achieved using the combination of the
alkylating compounds IA and IAA. We
(10) and others
(15,
23,
32–34)
have shown that controlled infusion can provide irreversible blockade of
desired energetic pathways with maintained preparation stability. In
mitochondria isolated from IA-treated hearts, we have found no loss of
oxidative capacity analyzed by ADP stimulated state 3 and 4
O2
(10) and isolated
mitochondrial oxidative capacity was not affected by the IA and IAA
concentrations used (see RESULTS). Moreover, by using CK
histochemistry, we have observed homogeneous patterns of CK inhibition within
tissue slices and myocytes from IA- and IAA-treated hearts
(10), indicating that 15 min
of infusion allows complete cellular distribution of IA. The activity of
another putative energy transfer enzyme, AK, remained unchanged in both IA and
IAA-treated hearts (see Table 1
and Refs. 10 and
34). Acute chemical inhibition
of CK gave the same result as targeted gene deletion of CK in knockout mice
(9,
10).
Blocking fatty acid usage, which is the preferred myocardial substrate in vivo, increases tmito in an ex vivo heart muscle preparation (45). The present ex vivo preparation, with glucose and pyruvate but no fatty acids as exogenous substrate, is therefore not representing the normal in vivo situation, but is appropriate to study the effect of glycolysis on tmito because it can be supplied with a high level of glucose and glycolysis is subsequently inhibited, whereas pyruvate provides for sustained energy metabolism.
Contractile function in absence of CK and/or glycolysis. Isolated
hearts in the present and other studies
(10,
15,
32–34)
treated with IA can maintain low to medium workloads with CK activity <10%
of baseline. This extends to MM and MM/mito CK knockout mice and rats with
phosphocreatine replaced with -guanidinopropionate in vitro
(29) and in vivo
(22). Unchanged CK fluxes are
observed during substrate deprivation
(12), hypoxia/cyanide infusion
(20), or three-fold increases
in work by pacing or catecholamine stress
(16).
The diastolic dysfunction indicated by EDP increases in IA and IAA hearts, respectively (see Table 2) may reflect elevated free [ADP] near myofibrils as measured using 31P NMR in IA-treated rat hearts (34). However, due to the importance of bound, compartmentalized CK in the myocardium (39, 44), increases in measured [ADP] may not reflect changes in subcompartments (20). Interestingly, blockade of glycolysis with IAA decreased left ventricular systolic pressure and increased end-diastolic pressure at baseline heart rate more than CK inhibition with IA, potentially pointing to the importance of glycolytic buffering of ATP near myofibrils in maintaining contractile function. Interestingly, if binding of glycolytic enzymes to the contractile elements in insect flight muscle is genetically disturbed, the capacity to fly in these animals is severely reduced (43).
The compromised contractile reserve observed after CK inhibition in the present study confirms previous observations in response to chronotropic (10), inotropic (34), and pressure-volume (15) cardiac work elevations. The report of functional loss due to glycolytic blockade is new to our knowledge. The equivalent reduction of contractile reserve in both IA- and IAA-treated hearts (Table 2) suggests the preferential use of glycolytically produced ATP during rapidly increased workloads. Such a function during dynamic exercise has been described for skeletal muscle (24). The reduced contractile reserve in hearts void of energetic buffers may be due to increased ADP affecting Ca2+ handling (32–34). The free energy of ATP hydrolysis is directly reduced after CK inhibition, affecting sarcoplasmic reticulum Ca2+ pumps (34) and CK blockade abolishes the increased cytosolic Ca2+ transient during inotropic stimulation (33).
Energy signaling speeds after CK and/or glycolysis inhibition. The significant reductions in tmito observed in response to glycolytic blockade alone and in combination with CK provides evidence that both of these energetic pathways act as cytosolic buffers that slow the metabolic signal to the mitochondria in response to dynamically varying ATP hydrolysis. The reduction in tmito with 0.4 mM IA treatment in the present study (40 ± 5%) compared favorably with that seen in our previous study (46 ± 6%) (10). The reduction in tmito by preferential glycolytic inhibition by IAA demonstrates the contribution of glycolysis in energy transfer, which was suggested previously (36, 37).
Pyruvate was added to the perfusate in the present experiments to provide oxidizable substrate in the absence of glycolysis. Positive inotropism of pyruvate has been demonstrated both in isolated myocytes (19) and intact hearts (11, 18, 47), causing improved cytosolic phosphorylation potential, redox state, and augmented intracellular Ca2+ transients under normal workload conditions. In the current study, pyruvate increased left ventricular systolic pressure at baseline heart rate versus glucose-only hearts (113 ± 5 vs. 90 ± 3 mmHg; P < 0.05) (10). Pretreatment tmito values in the present experiments with glucose + pyruvate are significantly shorter than for glucose-only hearts, as shown in Fig. 2 (4.3 ± 0.3 vs. 6.5 ± 0.5 s; P < 0.05) (10). We have previously observed pyruvate alone to lower tmito at 28°C versus glucose (35), but this was not in combination with glucose. This effect is probably not due to altered mitochondrial aerobic capacity, because the latter does not affect tmito (37).
Phosphofructokinase in inhibited by elevated citrate caused by pyruvate infusion (18) and GAPDH and pyruvate kinase action are also antagonized by pyruvate (42). Indeed, 2.5 mM pyruvate outcompetes 5 mM [13C]glucose, thereby limiting glycolysis to producing <2% of oxidative metabolism (3). Thus tmito appears to be quickened both by the inhibiting effects of pyruvate itself on glycolysis and by further iodoacetic acid blockade (Fig. 2).
In conclusion, there exists a complex system of bioenergetic buffering and signal transduction that includes not only the energy transfer enzymes CK (27, 28, 40) and AK (4, 25) but also the glycolytic pathway (3, 41). All of these systems affect the complex regulation of oxidative phosphorylation from the cytosol. The present findings show that inhibition of glycolytic buffering of phosphate metabolites (ADP/ATP/Pi) near ion pumps and myofibrils compromises contractile reserve during increased workloads and accelerates the transcytosolic energy signal for oxidative phosphorylation. The quicker ATP hydrolysis/synthesis coupling speeds during inhibition of glycolysis were further shortened when CK was additionally inhibited, without further deterioration of contractile reserve. We suggest that the faster energy transfer speeds observed during our dynamic workload steps in the absence of glycolytic buffering, alone or in combination with CK, reflects a function of glycolysis as a complementary temporal energy buffer in the cytosol that helps maintain myocardial contractility.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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-guanidinopropionate in perfused hearts and intact
rats. J Mol Cell Cardiol 31:
1845–1855, 1999.[ISI][Medline]
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P < 0.05
for pre- to posttreatment difference in tmito across all
heart rates vs. control pre-posttreatment difference; 
P <
0.05 for pre-posttreatment difference in tmito across all
heart rates vs. IAA-treated pre-posttreatment difference.