title: Synchrony of cardiomyocyte Ca(2+) release is controlled by T-tubule organization, SR Ca(2+) content, and ryanodine receptor Ca(2+) sensitivity.
abstract: Recent work has demonstrated that cardiomyocyte Ca(2+)release is desynchronized in several pathological conditions. Loss of Ca(2+) release synchrony has been attributed to t-tubule disruption, but it is unknown if other factors also contribute. We investigated this issue in normal and failing myocytes by integrating experimental data with a mathematical model describing spatiotemporal dynamics of Ca(2+) in the cytosol and sarcoplasmic reticulum (SR). Heart failure development in postinfarction mice was associated with progressive t-tubule disorganization, as quantified by fast-Fourier transforms. Data from fast-Fourier transforms were then incorporated in the model as a dyadic organization index, reflecting the proportion of ryanodine receptors located in dyads. With decreasing dyadic-organization index, the model predicted greater dyssynchrony of Ca(2+) release, which exceeded that observed in experimental line-scan images. Model and experiment were reconciled by reducing the threshold for Ca(2+) release in the model, suggesting that increased RyR sensitivity partially offsets the desynchronizing effects of t-tubule disruption in heart failure. Reducing the magnitude of SR Ca(2+) content and release, whether experimentally by thapsigargin treatment, or in the model, desynchronized the Ca(2+) transient. However, in cardiomyocytes isolated from SERCA2 knockout mice, RyR sensitization offset such effects. A similar interplay between RyR sensitivity and SR content was observed during treatment of myocytes with low-dose caffeine. Initial synchronization of Ca(2+) release during caffeine was reversed as SR content declined due to enhanced RyR leak. Thus, synchrony of cardiomyocyte Ca(2+) release is not only determined by t-tubule organization but also by the interplay between RyR sensitivity and SR Ca(2+) content.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Leiv
authors.initials: L
authors.lastname: Øyehaug
authors.forename: Kristian Ø
authors.initials: KØ
authors.lastname: Loose
authors.forename: Guro F
authors.initials: GF
authors.lastname: Jølle
authors.forename: Åsmund T
authors.initials: ÅT
authors.lastname: Røe
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Ole M
authors.initials: OM
authors.lastname: Sejersted
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D003600:Cytosol / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism / Q000648:ultrastructure*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium