Beta-Adrenergic Stimulation Maintains Cardiac Function in Serca2 Knockout Mice

Abstract

Previous studies on Serca2 knockout (KO) mice showed that cardiac function is sustained in vivo for several weeks after knockout, whereas SERCA protein levels decrease and calcium dynamics are significantly impaired. In this study, we reconcile observed cellular and organ level contractile function using a cardiac multiscale model. We identified and quantified the changes in cellular function that are both consistent with observations and able to compensate for the decrease in SERCA. Calcium transients were used as input for multiscale computational simulations to predict whole-organ response. Although this response matched experimental pressure-volume (PV) measurements in healthy mice, the reduced magnitude calcium transients observed in KO cells were insufficient to trigger ventricular ejection. To replicate the effects of elevated catecholamine levels observed in vivo, cells were treated with isoproterenol. Incorporation of the resulting measured β-adrenergically stimulated calcium transients into the model resulted in a close match with experimental PV loops. Changes in myofilament properties, when considered in isolation, were not able to increase tension development to levels consistent with measurements, further confirming the necessity of a high β-adrenergic state. Modeling additionally indicated that increased venous return observed in the KO mice helps maintain a high ejection fraction via the Frank-Starling effect. Our study shows that increased β-adrenergic stimulation is a potentially highly significant compensatory mechanism by which cardiac function is maintained in Serca2 KO mice, producing the increases in both systolic and diastolic calcium, consistent with the observed contractile function observed in experimental PV measurements.

Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

“…The difference between in vivo and ex vivo cardiac function clearly points to the presence of compensatory systemic changes that support cardiac output in SERCA2 KO mice, such as increased circulating plasma norepinephrine (3). Our findings are further supported by a recent study from Land et al (21), where it was reported that the low amplitude of the Ca 2ϩ transients observed in KO cardiomyocytes were insufficient to trigger ventricular ejection when the recorded Ca 2ϩ transients from both 4-and 7-wk KO mice were used in a multiscale computational simulator of the whole heart response. Based on data obtained from ␤-adrenergic enhancement of Ca 2ϩ transients, and assuming increased venous return (as a consequence of elevated circulating catecholamine levels and the Frank-Starling effect), Land et al (21) reported that the simulated P-V loops were comparable with those obtained from in situ experiments.…”

“…Our findings are further supported by a recent study from Land et al (21), where it was reported that the low amplitude of the Ca 2ϩ transients observed in KO cardiomyocytes were insufficient to trigger ventricular ejection when the recorded Ca 2ϩ transients from both 4-and 7-wk KO mice were used in a multiscale computational simulator of the whole heart response. Based on data obtained from ␤-adrenergic enhancement of Ca 2ϩ transients, and assuming increased venous return (as a consequence of elevated circulating catecholamine levels and the Frank-Starling effect), Land et al (21) reported that the simulated P-V loops were comparable with those obtained from in situ experiments. This suggests that the increased ␤-adrenergic state contributes to maintain cardiac output in vivo in KO mice and may also explain why the ex vivo KO heart (in the absence of ␤-adrenergic stimuli and perfused under constant preload conditions) does not demonstrate elevated end-diastolic pressure, as demonstrated in vivo (3).…”

A computational pipeline for quantification of mouse myocardial stiffness parameters

“…The pressure-volume relationship was quite linear within the interval of applied pressures (Fig. 7a), in agreement with previous in vivo work [31], [32]. The mesh corresponding to zero and maximum pressures are shown in Fig.…”

Cardiac muscle regulatory units are predicted to interact stronger than neighboring cross-bridges

“…Tropomyosin was modeled as an elastic string with a given stiffness and pre-defined deformation states allowing us to incorporate the energy of mechanical deformation into the free energies of the ensemble states. This is similar to several studies on modeling of cooperativity 5,29,30 . As derived earlier 12 , our geometrical model resulted in a relationship between U T;W , U W;S , and U T;S with one of the free energies determined by the other two.…”