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  • Title: Energetic state is a strong regulator of sarcoplasmic reticulum Ca2+ loss in cardiac muscle: different efficiencies of different energy sources.
    Author: Kuum M, Kaasik A, Joubert F, Ventura-Clapier R, Veksler V.
    Journal: Cardiovasc Res; 2009 Jul 01; 83(1):89-96. PubMed ID: 19389722.
    Abstract:
    AIMS: Increased diastolic sarcoplasmic reticulum (SR) Ca(2+) loss could depress contractility in heart failure. Since the failing myocardium has impaired energetics, we investigated whether Ca(2+) 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 Ca(2+)-free solution. In ventricular fibres caffeine-induced tension transients under optimal energetic conditions were used to estimate SR [Ca(2+)]. In cardiomyocytes, intra-SR Ca(2+) was monitored by use of the fluorescent marker Mag-fluo 4. In fibres, SR Ca(2+) 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 Ca(2+)-ATPase (SERCA) inhibitors cyclopiazonic acid or 2,5-di(tert-butyl)-1,4-benzohydroquinone significantly decreased Ca(2+) loss. At 100 nM external [Ca(2+)], the SR Ca(2+) loss was also energy dependent and was not significantly inhibited by tetracaine. In cardiomyocytes, the decline in SR [Ca(2+)] at zero external [Ca(2+)] was almost two times slower under optimal energetic conditions than in the presence of exogenous ATP only. CONCLUSION: At low extra-reticular [Ca(2+)], the main leak pathway is an energy-sensitive backward Ca(2+) pump, and direct mitochondrial-SERCA ATP channelling is more effective in leak prevention than local ATP generation by bound CK.
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