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CK inhibition accelerates transcytosolic energy signaling during rapid workload steps in isolated rabbit hearts
G J Harrison1, M H van Wijhe, B de Groot
1Laboratory for Physiology, Institute for Cardiovascular Research, Free University, 1081BT Amsterdam, The Netherlands.
Abstract:
The effect of graded creatine kinase (CK) inhibition on the response time of mitochondrial O2 consumption to dynamic workload jumps (tmito) was studied in isolated rabbit hearts. Tyrode-perfused hearts (n = 7/group) were exposed to 15 min of 0, 0.1, 0.2, or 0.4 mM iodoacetamide (IA) (CK activity = 100, 14, 6, and 3%, respectively). Pretreatment tmito was similar across groups at 6.5 +/- 0.5 s (mean +/- SE). The increase observed over time in control hearts (33 +/- 8%) was progressively reversed to 16 +/- 6, -20 +/- 6 (P < 0.01 vs. control), and -46 +/- 6 (P < 0.01 vs. control) % in the 0.1, 0.2 and 0.4 mM IA groups, respectively. The faster response times occurred without reductions in mitochondrial oxidative capacity (assessed in vitro) or myocardial O2 consumption of the whole heart during workload steps. Isovolumic contractile function assessed as rate-pressure product (RPP) and contractile reserve (increase in RPP during heart rate steps) were significantly reduced by IA. We conclude that CK in the myofibrils and/or cytosol does not speed up transfer of the energy-related signal to the mitochondria but rather acts as an energetic buffer, effectively slowing the stimulus between myofibrils/ion pumps and oxidative phosphorylation. This argues against the existence of an obligatory creatine phosphate energy shuttle, because CK is effectively bypassed.
Insights
Creatine kinase (CK) inhibition in rabbit hearts did not speed mitochondrial oxygen use response but acted as an energy buffer. This challenges the idea of a direct creatine phosphate energy shuttle.
Area of Science:
- Physiology
- Biochemistry
- Cardiovascular Research
Background:
- Creatine kinase (CK) plays a crucial role in cellular energy buffering and transfer.
- The precise role of CK in modulating the dynamic response of mitochondrial respiration remains incompletely understood.
Purpose of the Study:
- To investigate the effect of graded creatine kinase inhibition on the response time of mitochondrial O2 consumption to workload changes in isolated rabbit hearts.
- To determine if CK facilitates rapid energy signal transmission to mitochondria or acts as an energetic buffer.
Main Methods:
- Isolated rabbit hearts were perfused with Tyrode solution and exposed to varying concentrations of iodoacetamide (IA) to inhibit CK activity.
- The response time of mitochondrial O2 consumption (tmito) to dynamic workload jumps was measured.
- Myocardial O2 consumption, mitochondrial oxidative capacity, and contractile function (rate-pressure product) were assessed.
Main Results:
- Progressive inhibition of CK activity led to significantly faster response times of mitochondrial O2 consumption to workload jumps.
- These faster responses occurred without compromising mitochondrial oxidative capacity or overall myocardial O2 consumption.
- Contractile function and reserve were significantly impaired by CK inhibition.
Conclusions:
- CK in the myofibrils and/or cytosol functions as an energetic buffer, not a facilitator of rapid energy signal transfer to mitochondria.
- The findings suggest that CK slows the energetic stimulus transmission between myofibrils/ion pumps and oxidative phosphorylation.
- This study provides evidence against an obligatory creatine phosphate energy shuttle mechanism, as CK appears to be bypassed in this context.