Synchrony of Cardiomyocyte Ca2+ Release is Controlled by t-tubule Organization, SR Ca2+ Content, and Ryanodine Receptor Ca2+ 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.

T-tubule remodeling and increased heterogeneity of calcium release during the progression to heart failure in intact rat ventricle

“…A diminished TT network has been characterized as a contributing factor to phenotypic changes seen during HF, such as Ca 2+ transients that are slower and have a smaller amplitude; however, these changes have been recently attributed to TT remodeling, rather than detubulation (Brette and Orchard ; Oyehaug et al. ; Song et al. ; Louch et al.…”

“…This signaling is mediated via Ca 2+ ‐induced‐Ca 2+ release and leads to local release events referred to as Ca 2+ sparks (Oyehaug et al. ; Zhang et al. ).…”

Imipramine as an alternative to formamide to detubulate rat ventricular cardiomyocytes

“…CaT and Ca 2+ alternans confirming that the T-tubules are critical to ensure normal and rapid, synchronized Ca 2+ release (Brette et al, 2002(Brette et al, , 2005Caldwell et al, 2014;Frisk et al, 2016;Oyehaug et al, 2013 …”

New Insights in Cardiac Calcium Handling and Excitation-Contraction Coupling

“…The specific organization of ion channels on the plasma membrane, and in particular on the specialized invaginations of the T-tubules, plays a pivotal role in EC coupling (Oyehaug et al 2013; Galbiati et al 2001). Indeed, the loss of these structures leads to aberrant Ca 2+ handling with blunted contractility, and such alteration has been mechanistically associated to HF (Wei et al 2010).…”