https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33017 ~ATP), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ΔG_~ATP. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ΔG_~ATP to a level that is not sufficient to maintain normal function of sarcoplasmic Ca²⁺-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ΔG_~ATP with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux.]]> Wed 24 Nov 2021 15:52:41 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34969 d = 121 ± 14 nM. Ex-vivo phosphorylation/dephosphorylation experiments suggested that the divergent CaM regulation of healthy and failing human RyR2 was caused by differences in RyR2 phosphorylation by protein kinase A and Ca-CaM-dependent kinase II. Ca²⁺-spark measurements in murine cardiomyocytes harbouring RyR2 phosphomimetic or phosphoablated mutants at S2814 and S2808 suggest that phosphorylation of residues corresponding to either human RyR2-S2808 or S2814 is both necessary and sufficient for RyR2 regulation by CaM. Our results challenge the current concept that CaM universally functions as a canonical inhibitor of RyR2 across species. Rather, CaM's biological action on human RyR2 appears to be more nuanced, with inhibitory activity only on phosphorylated RyR2 channels, which occurs during exercise or in patients with heart failure.]]> Wed 24 Jun 2020 11:42:42 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:9917 Sat 24 Mar 2018 08:13:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:9879 Sat 24 Mar 2018 08:12:48 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20246 2+_-dependent gating of ryanodine receptors (RyRs) in the sarco/endoplasmic reticulum (SR) and is critical for cardiac excitation–contraction coupling. This process is seen as Ca²⁺ sparks, which reflect the concerted gating of groups of RyRs in the dyad, a specialised junctional signalling domain between the SR and surface membrane. However, the mechanism(s) responsible for the termination of regenerative CICR during the evolution of Ca²⁺ sparks remain uncertain. Rat cardiac RyR gating was recorded at physiological Ca²⁺, Mg²⁺ and ATP levels and incorporated into a 3D model of the cardiac dyad which reproduced the time-course of Ca²⁺ sparks, Ca²⁺ blinks and Ca²⁺ spark restitution. Model CICR termination was robust, relatively insensitive to the number of dyadic RyRs and automatic. This emergent behaviour arose from the rapid development and dissolution of nanoscopic Ca²⁺ gradients within the dyad. These simulations show that CICR does not require intrinsic inactivation or SR calcium sensing mechanisms for stability and cessation of regeneration that arises from local control at the molecular scale via a process we call ‘induction decay’.]]> Sat 24 Mar 2018 07:59:55 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17918 Sat 24 Mar 2018 07:56:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33274 Mon 24 Sep 2018 13:26:22 AEST ]]>