Energetic state is a strong regulator of sarcoplasmic reticulum Ca2+ loss in cardiac muscle: different efficiencies of different energy sources

M. Kuum , A. Kaasik , F. Joubert , R. Ventura-Clapier , V. Veksler

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Cardiovasc. Res., 83, 1
Published 01 Jul. 2009
DOI: 10.1093/cvr/cvp125
ISSN: 0008-6363


Aims Increased diastolic sarcoplasmic reticulum (SR) Ca2+ loss could depress contractility in heart failure. Since the failing myocardium has impaired energetics, we investigated whether Ca2+ loss is linked to changes in energetic pathways. Methods and results Leakage from SR in mouse permeabilized preparations was assessed using exogenous ATP, ATP + phosphocreatine (activation of bound creatine kinase, CK), ATP + mitochondrial substrates (mitochondrial activation), or with all of these together (optimal energetic conditions) in Ca2+-free solution. In ventricular fibres caffeine-induced tension transients under optimal energetic conditions were used to estimate SR {[}Ca2+]. In cardiomyocytes, intra-SR Ca2+ was monitored by use of the fluorescent marker Mag-fluo 4. In fibres, SR Ca2+ content after 5 min incubation strongly depended on energy supply (100\%-optimal energetic conditions; 27 +/- 5\%-exogenous ATP only, 52 +/- 5\%-endogenous CK activation; 88 +/- 8\%-mitochondrial activation, P < 0.01 vs. CK system). The significant loss with only exogenous ATP was not inhibited by the ryanodine receptor blockers tetracaine or ruthenium red. However, the SR Ca2+-ATPase (SERCA) inhibitors cyclopiazonic acid or 2,5-di(tert-butyl)-1,4-benzohydroquinone significantly decreased Ca2+ loss. At 100 nM external {[}Ca2+], the SR Ca2+ loss was also energy dependent and was not significantly inhibited by tetracaine. In cardiomyocytes, the decline in SR {[}Ca2+] at zero external {[}Ca2+] was almost two times slower under optimal energetic conditions than in the presence of exogenous ATP only. Conclusion At low extra-reticular {[}Ca2+], the main leak pathway is an energy-sensitive backward Ca2+ pump, and direct mitochondrial-SERCA ATP channelling is more effective in leak prevention than local ATP generation by bound CK.