A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca2+ transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca2+ handling, Ca2+, K+ and Cl− currents, and Na+/K+-ATPase properties were included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca2+ sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca2+ transient amplitude and kinetics. It also replicated the behavior of force-Ca2+, release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca2+ channels or phospholamban limited Ca2+ transients and contractile responses in parallel, while blocking phospholemman and K+ channel (IKs) effects enhanced Ca2+ and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca2+ (due to greater Ca2+ buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca2+ transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa vs. XBcy have greater impact on isometric vs. isotonic contraction, respectively.

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Key pointsr Mice with Ca 2+ -calmodulin-dependent protein kinase (CaMKII) constitutive pseudo-phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D +/+ mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca 2+ leak in diastole and increased propensity to arrhythmias under stress conditions. r We generated phospholamban (PLN)-deficient S2814D r A mathematical human myocyte model replicates these results and predicts the increase in SR Ca 2+ uptake required to prevent the arrhythmias induced by a CaMKII-dependent leaky RyR2.Abstract Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D +/+ ) have increased propensity to arrhythmias under β-adrenergic stress conditions. Although abnormal Ca 2+ release from the sarcoplasmic reticulum (SR) has been linked to arrhythmogenesis, the role played by SR Ca 2+ uptake remains controversial. We tested the hypothesis that an increase in SR Ca 2+ uptake is able to rescue the increased arrhythmia propensity of S2814D +/+ mice. We generated phospholamban (PLN)-deficient/S2814D +/+ knock-in mice by crossing two colonies, S2814D

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