Nutrient restriction preserves calcium cycling and mitochondrial function in cardiac myocytes during ischemia and reperfusion

Abstract

Nutrient restriction (NR) prolongs longevity via enhanced mitochondrial function. To test the hypothesis that NR enhances resistance to ischemia/reperfusion (IR) arrhythmias via preserved calcium (Ca) cycling and mitochondrial function. We examined the protective effects of NR on regional IR in cultured neonatal rat ventricular myocyte monolayers. Optical mapping of intracellular Ca and mitochondrial membrane potential Δψm was performed using Rhod 2-AM and TMRE, respectively. Regional ischemia was mimicked by covering a portion of monolayer with a glass coverslip until loss of Ca propagation, and reperfusion was mimicked by removing the coverslip. NR was mimicked by culture in serum- and glucose-free medium for 24 hours. Relative to controls, NR monolayers sustained Ca oscillations during longer periods of ischemia (19.2±1.8 min vs 10.4±1.4 min, p < 0.001); attenuated increases in Ca transient duration (CaD) and time decay Constant (Tau) during ischemia; preserved Conduction velocity (CV) during early reperfusion, leading to protection against reperfusion arrhythmias; had minimal “rebound” decreased CaD and Tau during reperfusion; and had no depolarization of Δψm during IR. NR attenuates IR arrhythmias via 1) stable calcium cycling; and 2) prevention of Δψm depolarization during IR. Enhanced mitochondrial resistance to IR arrhythmias may play a role in NR-induced longevity prolongation.

Mitochondrial instability during regional ischemia–reperfusion underlies arrhythmias in monolayers of cardiomyocytes

“…The coverslip IR model in the NRVM monolayer, originally developed by Pitts and Toombs [29], meets these criteria in several important ways: it creates a regional ischemic microenvironment that not only limits cellular access to oxygen and substrates, but also results in a restricted extracellular space, within which ischemic metabolites (e.g., lactate) and ions (H + , K + ) accumulate, just as in the ischemic heart. Moreover, the ability to simulate reperfusion and study the interface between the ischemic and non-ischemic cells in the monolayer allows one to examine the effects of heterogeneity in the excitable medium, essential for understanding the origin of arrhythmias, as demonstrated in previous optical mapping studies [30, 37]. An additional advantage realized in the present work is that the functional impact of IR at the macroscopic (whole monolayer) and microscopic (subcellular) level can be investigated.…”

“…Slow recovery of Cx43 phosphorylation was considered to be a major arrhythmogenic factor during early reperfusion. Later, Wang et al showed the protective effects of nutrition restriction preconditioning against IR using the same model [37]; post-ischemic mitochondrial depolarization was prevented and IR-induced arrhythmias were decreased, although the subcellular dynamics of ΔΨ m were not investigated. Our high resolution observations of the mitochondrial dynamics during IR, in the present work, strongly support the hypothesis that mitochondrial ΔΨ m instability plays a major role in post-ischemic arrhythmias.…”

Cardiac Overexpression of S100A6 Attenuates Cardiomyocyte Apoptosis and Reduces Infarct Size After Myocardial Ischemia‐Reperfusion

“…Although S100A6 gene therapy provided a survival advantage after I/R, the challenge for translating this to clinical practice will be optimizing gene delivery for rapid transfection prior to or immediately after reperfusion. The exact mechanism behind this protective effect is unclear; however, we can speculate that the enhanced Ca 2+ cycling would attenuate diastolic Ca 2+ overload, thus suppressing arrhythmogenesis and leading to a reduction in reperfusion arrhythmias . All mortality occurred during occlusion or immediately on reperfusion, supporting an arrhythmic death.…”

“…The exact mechanism behind this protective effect is unclear; however, we can speculate that the enhanced Ca 2+ cycling would attenuate diastolic Ca 2+ overload, thus suppressing arrhythmogenesis and leading to a reduction in reperfusion arrhythmias. 32,33 All mortality occurred during occlusion or immediately on reperfusion, supporting an arrhythmic death.…”

Does Chronic Cola Consumption Increase Urinary Stone Risk? Evidence from the <i>Drosophila</i> Model of Urolithiasis

“…Cola contains glucose/fructose, caffeine, water and some confidential components [29]. Long-term consumption of high sugar beverages may contribute to many diseases such as insulin resistance, obesity, hypertensive cardiovascular disease, and kidney disease [30]. However, there was no reported association of the cola with patients' health [31,32].…”