Age-related pacemaker deterioration is due to impaired intracellular and membrane mechanisms: Insights from numerical modeling

Figures

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  Figure 1.. Age-associated deficient pacemaker function. (A) Age-associated reduction in basal beating interval and sensitivity to PDE inhibition by IBMX and β-AR stimulation by ISO. Note that the maximal beating rate is restored in response to maximal IBMX or ISO concentration (adapted from Yaniv et al. [2016]). Data are presented as mean ± SD. (B) Age-associated reduction in L-type, T-type, and HCN current conductance (adapted from Larson et al. [2013]) shown for sinoatrial node myocytes in mice aged 2–3 mo (black), 21–24 mo (green), and 28 mo (red) in the absence (filled circles) and presence (open circles) of 1 µM ISO. Data are presented as average ± SEM. (C) Age-associated reduced LCR ensemble, SERCA, and RyR2 presence (adapted from Liu et al. [2014]). From top to bottom: mean amplitudes of Ca2+ signals of the LCR ensemble (integrated Ca2+ signal produced by each LCR); representative Western blots of SAN (protein expression), atrial and ventricular tissues from adult (2–4 mo) and aged (24–27 mo) mice normalized to sarcomeric actin levels; RyR protein levels. Data are presented as mean ± SD. (top) *, P < 0.05 versus adult, mixed effects model for repeated measure ANOVA; (middle) *, P <…

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  Figure 2.. Model parameters adjustment. (A) Schematic illustration of the AC-AC-cAMP-PKA signaling cascade. AC is activated by adrenergic receptors (β-AR) and calmodulin and deactivated by cholinergic receptor (ChR) stimulation. Activated AC converts ATP into cAMP, which itself is transformed into PKA. PKA phosphorylates several targets, including PLB proteins, whose phosphorylation level will regulate the activation of SERCA and thus the rate at which Ca2+ enters the SR. The model includes two restraining mechanisms that act like brakes: protein phosphatase (PPT), which removes phosphate groups from proteins, and PDE, which breaks the phosphodiester bond in cAMP and degrades its level. (B) If shift in the I–V curve as a function of cAMP in adult and aged mice. Basal state (V shift = 0 and [cAMP] = 20 pmol/mg protein). The maximal shift for adult and aged mice was taken from the experimental results of Sharpe et al. (2017). (C) PLBp modulation of SERCA in adult and aged mice. The expressions for adult and aged mice are empirical.

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  Figure 3.. Model simulation in response to changes occurring with aging. Coupled-clock function of adult mice (blue), aged mice when only changes in the M clock mechanisms were taken into account (red), aged mice when only changes in the Ca2+ clock mechanisms were taken into account (yellow), and aged mice when changes in both M and Ca2+ clock mechanisms were included (purple). Membrane voltage, main membrane currents, AC-cAMP-PKA signaling, and Ca2+ cycling (flux and concentration) in the SR in adult and aged mice: membrane voltage (Vm; A); cAMP level (B); PKA activity level (C); flux of Ca2+ existing in the SR (jSRCarel; D); Ca2+ concentration in the junctional SR compartment (CajSR; E); the Na+-Ca2+ exchanger current (INCX; F); HCN current (If; G; L-type current (ICaL; H); and T-type Ca2+ current (ICaT; I).

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  Figure 4.. Parameter sensitivity to Pup and V0.5. The effect of changes in Pup and V0.5 on AP firing rate. V0.5 refers to the half activation voltage of the HCN current, If.

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  Figure 5.. Major currents in adult and aged mice. Modification in specific membrane and sarcoplasmic proteins (ICaT, RyR, If) modified the other proteins. (A) Membrane voltage (Vm). (B) 1.2 L-type current (ICaL1.2). (C) 1.3 L-type current (ICaL1.2). (D) Rapidly activating delayed rectifier K+ current (IKr). (E) HCN current. (F) Inward rectifying K+ current (IK1). (G) Sodium current (INa1.1). (H) Sodium current (INa1.5). (I) T-type Ca2+ current (ICaT). (J) Na+-Ca2+ exchanger current (INaCa). (K) Na+-K+ pump current (INaK). (L) 4-aminopyridine–sensitive currents (Ito).

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  Figure 6.. Mean AP firing rate changes in response to drug perturbations. Simulated AP firing rate in absolute numbers (A) and percentage change from the adult basal firing rate (B) of young and adult mouse SAN cells under ISO (1,000 µM), caged cAMP release, or IBMX treatment (3,000 µM). In B, the red bars show the experimental range (defined as mean ± twice the SEM) of the decrease in AP firing rate in aged cells with respect to the adult basal rate, as reported in Larson et al. (2013), Liu et al. (2014), and Sharpe et al. (2017).

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  Figure 7.. Model simulation in response to pacemaker function changes occurring in response to ISO in adult and aged mice. In response to maximal concentration of ISO, AP firing rate (A), cAMP (B), and PKA activities (C) are restored; the flux of Ca2+ in the SR (jSRCarel; D) and Ca2+ concentration in the junctional sarcoplasmic reticulum compartment (CajSR; E) are compensated for; and the Na+-Ca2+ exchanger current (INCX; F), HCN current (If; G), L-type current (ICaL; H), and T-type Ca2+ current (ICaT; I) are completely or partly restored.

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  Figure 8.. Model simulation in response to pacemaker function changes occurring in response to IBMX in adult and aged mice. In response to maximal concentration of IBMX, AP firing rate (A), cAMP (B), and PKA (C) activities are restored; the flux of Ca2+ existing the SR (jSRCarel; D) and Ca2+ concentration in the junctional sarcoplasmic reticulum compartment (CajSR; E) are compensated for; and the Na+-Ca2+ exchanger current (INCX; F), HCN current (If; G), L-type current (ICaL; H), and T-type Ca2+ current (ICaT; I) are completely or partly restored.

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  Figure 9.. Age-associated basal AP firing rate can be reversed. (A) 167 nM ISO can reverse the aged basal AP firing rate to that of adult mouse pacemaker cells. (B) 50 µM IBMX can also reverse the aged basal AP firing rate to that of adult mouse pacemaker cells.

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  Figure 10.. Sensitivity of AP firing rate to drug perturbations. (A and B) Simulation of beating interval dynamics in response to PDE inhibition by ISO (A) or IBMX (B).

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  Figure 11.. Overexpression of AC1 or AC8 restores the age-associated reduction in AP firing rate. Increase in KAC can restore the age-associated reduction in AP firing rate.