-
Views
-
Cite
Cite
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, Volume 83, Issue 1, 1 July 2009, Pages 89–96, https://doi.org/10.1093/cvr/cvp125
Close - Share Icon Share
Abstract
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.
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.
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.
