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

Malle Kuum (1) , Allen Kaasik (1) , Frederic Joubert (2) , Renée Ventura-Clapier (3) , Vladimir Veksler (2)

1 Department of Pharmacology [Tartu, Estonie]
2 Signalisation et physiopathologie cardiaque
3 CARPAT (UMRS1180) - Signalisation et physiopathologie cardiovasculaire

Time for primary review: 20 days 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.

Keywords: Energy metabolism; Sarcoplasmic reticulum; Calcium homeostasis; Mitochondria; Creatine kinase

Domains: Life Sciences [q-bio]

Malle Kuum, Allen Kaasik, Frederic Joubert, Renée Ventura-Clapier, Vladimir Veksler. Energetic state is a strong regulator of sarcoplasmic reticulum Ca2+ loss in cardiac muscle: different efficiencies of different energy sources. Cardiovascular Research, 2009, 83 (1), pp.89-96. ⟨10.1093/cvr/cvp125⟩. ⟨hal-04089168⟩