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1 Heart Foundation Research Centre, Griffith University, Gold Coast, Queensland, Australia; Laboratory for Physiology, Vrije Universiteit, Amsterdam, The Netherlands
2 Laboratory for Physiology, Vrije Universiteit, Amsterdam, The Netherlands
3 Department of Molecular Cell Physiology, Vrije Universiteit, Amsterdam, The Netherlands; Laboratory for Physiology, Vrije Universiteit, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: hans.van.beek{at}falw.vu.nl.
Creatine kinase (CK) and glycolysis (G) represent important energy buffering processes in the cardiac myocyte. While the role of compartmentalized creatine kinase in energy transfer has been intensely investigated, similar duties for intracellular glycolysis have not been demonstrated. By measuring the response time of mitochondrial oxygen consumption to dynamic work load jumps (tmito) in isolated rabbit hearts, we studied the effect of inhibiting energetic systems (CK and/or G) on transcytosolic signal transduction that couples cytosolic ATP hydrolysis to activation of oxidative phosphorylation. Tyrode-perfused hearts were exposed to 15 min of: (a) 0.4 mM iodoacetamide (IA, n=6) to block CK, (CK activity <3% vs control), (b) 0.3 mM iodoacetic acid (IAA, n=5) to inhibit G, (GAPDH activity <3% vs control), or (c) vehicle (control, n=7) at 37°C. Pre-treatment tmito was similar across groups at 4.3 ± 0.3 seconds (mean ± SEM). No change in tmito was observed in control hearts, however in IAA and IA treated hearts, tmito decreased by 15 ± 3%* and 40 ± 5%* respectively, (* P<0.05 vs control), indicating quicker energy supply-demand signalling in the absence of ADP/ATP buffering by CK or G. The faster response times in IAA and IA groups were independent of the size of the work load jump, and the increase in myocardial oxygen consumption during work load steps was unaffected by CK or G 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]. 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 work loads. Glycolysis may therefore play a similar role as creatine kinase in heart muscle.
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