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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 23, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp125
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

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

Malle Kuum1,2,3, Allen Kaasik1,2,3, Frederic Joubert1,2, Renée Ventura-Clapier1,2 and Vladimir Veksler1,2,*

1 INSERM, U-769, Châtenay-Malabry F-92296, France
2 Univ Paris-Sud, Châtenay-Malabry F-92296, France
3 Department of Pharmacology, Centre of Molecular and Clinical Medicine, University of Tartu, Estonia

* To whom correspondence should be addressed at: U-769 INSERM, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France. Tel.: (33-1) 46.83.57.63. Fax: (33-1) 46.83.54.75. E-mail: Vladimir.VEKSLER{at}cep.u-psud.fr

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.: 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 fibers 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.

Results.: In fibers, 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 (TBQ) 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.

Conclusions.: At low extrareticular [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.

Time for primary review: 20 Days


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