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

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

Creatine kinase (CK) 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 = 6) to block CK (CK activity <3% vs. control), 2) 0.3 mM iodoacetic acid (IAA; n = 5) to inhibit glycolysis (GAPDH activity <3% vs. control), or 3) vehicle (control, n = 7) at 37°C. Pretreatment t_mito was similar across groups at 4.3 ± 0.3 s (means ± SE). No change in t_mito was observed in control hearts; however, in IAA- and IA-treated hearts, t_mito decreased by 15 ± 3% and 40 ± 5%, respectively (P < 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 ± 8% and 80 ± 10% of baseline, respectively (P < 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

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