Cardiac expression and location of hexokinase changes in a mouse model of pure creatine deficiency

Branovets, Jelena; Karro, Niina; Barsunova, Karina; Laasmaa, Martin; Lygate, Craig A.; Vendelin, Marko; Birkedal, Rikke

doi:10.1152/ajpheart.00188.2020

Cited by 5 publications

(18 citation statements)

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“…The heart can utilize glucose, lactate, fatty acids, and creatine for maintaining energy supply (Neubauer, 2007;Branovets et al, 2021). The decrease of blood lactate may thus indicate an increased anaerobic energy demand triggered by hypoxia, which cannot be buffered by cellular stores of creatine/phosphocreatine in the heart of Agat −/− mice as previously shown in hypoxic muscle tissue of these mice (Nabuurs et al, 2013).…”

Section: Discussionmentioning

confidence: 92%

Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

et al. 2021

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Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltransferase. Low hArg concentrations are associated with cardiovascular morbidity and predict mortality in patients with PH. We therefore aimed to investigate the survival and cardiac outcome of AGAT knockout (Agat−/−) mice under hypoxia and a possible rescue of the phenotype.Methods:Agat−/− mice and wild-type (WT) littermates were subjected to normoxia or normobaric hypoxia (10% oxygen) for 4 weeks. A subgroup of Agat−/− mice was supplemented with 1% creatine from weaning. Survival, hematocrit, blood lactate and glucose, heart weight-to-tibia length (HW/TL) ratio, hArg plasma concentration, and Agat and Gamt expression in lung, liver, and kidneys were evaluated.Results: After 6 h of hypoxia, blood lactate was lower in Agat−/−-mice as compared to normoxia (p < 0.001). Agat−/− mice died within 2 days of hypoxia, whereas Agat−/− mice supplemented with creatine and WT mice survived until the end of the study. In WT mice, hematocrit (74 ± 4 vs. 55 ± 2%, mean ± SD, p < 0.001) and HW/TL (9.9 ± 1.3 vs. 7.3 ± 0.7 mg/mm, p < 0.01) were higher in hypoxia, while hArg plasma concentration (0.25 ± 0.06 vs. 0.38 ± 0.12 μmol/L, p < 0.01) was lower. Agat and Gamt expressions were differentially downregulated by hypoxia in lung, liver, and kidneys.Conclusion:Agat and Gamt are downregulated in hypoxia. Agat−/− mice are nonviable in hypoxia. Creatine rescues the lethal phenotype, but it does not reduce right ventricular hypertrophy of Agat−/− mice in hypoxia.

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Section: Discussionmentioning

confidence: 92%

Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

et al. 2021

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“…Expression was analysed as in Branovets et al. (2021) and Laasmaa et al. (2021), with the exception that the staining intensity was quantified using ImageJ.…”

Section: Methodsmentioning

confidence: 99%

“…AGAT and GAMT mice were genotyped as in Branovets et al (2013Branovets et al ( , 2021 and Laasmaa et al (2021).…”

Section: Genotypingmentioning

confidence: 99%

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Cardiomyocytes from female compared to male mice have larger ryanodine receptor clusters and higher calcium spark frequency

Laasmaa,

Branovets,

Stolova

et al. 2023

The Journal of Physiology

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Sex differences in cardiac physiology are receiving increased attention as it has become clear that men and women have different aetiologies of cardiac disease and require different treatments. There are experimental data suggesting that male cardiomyocytes exhibit larger Ca2+ transients due to larger Ca2+ sparks and a higher excitation–contraction coupling gain; in addition, they exhibit a larger response to adrenergic stimulation with isoprenaline (ISO). Here, we studied whether there are sex differences relating to structural organization of the transverse tubular network and ryanodine receptors (RyRs). Surprisingly, we found that female cardiomyocytes exhibited a higher spark frequency in a range of spark magnitudes. While overall RyR expression and phosphorylation were the same, female cardiomyocytes had larger but fewer RyR clusters. The density of transverse t‐tubules was the same, but male cardiomyocytes had more longitudinal t‐tubules. The Ca2+ transients were similar in male and female cardiomyocytes under control conditions and in the presence of ISO. The synchrony of the Ca2+ transients was similar between sexes as well. Overall, our data suggest subtle sex differences in the Ca2+ influx and efflux pathways and their response to ISO, but these differences are balanced, resulting in similar Ca2+ transients in field‐stimulated male and female cardiomyocytes. The higher spark frequency in female cardiomyocytes is related to the organization of RyRs into larger, but fewer clusters. imageKey points During a heartbeat, the force of contraction depends on the amplitude of the calcium transient, which in turn depends on the amount of calcium released as calcium sparks through ryanodine receptors in the sarcoplasmic reticulum. Previous studies suggest that cardiomyocytes from male compared to female mice exhibit larger calcium sparks, larger sarcoplasmic reticulum calcium release and greater response to adrenergic stimulation triggering a fight‐or‐flight response. In contrast, we show that cardiomyocytes from female mice have a higher spark frequency during adrenergic stimulation and similar spark morphology. The higher spark frequency is related to the organization of ryanodine receptors into fewer, but larger clusters in female compared to male mouse cardiomyocytes. Despite subtle sex differences in cardiomyocyte structure and calcium fluxes, the differences are balanced, leading to similar calcium transients in cardiomyocytes from male and female mice.

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“…In fibres from CK KO mice lacking both the cytosolic and mitochondrial CK isoforms, the apparent K M ADP was lower than in WT, and mitochondria seemed to intercalate between the myofibrils [ 104 ]. However, in cardiomyocytes from creatine-deficient GAMT KO mice, where the CK system is inhibited by lack of creatine, the apparent K M ADP as well as mitochondrial organization was the same as in WT littermates [ 105 ], and there were no changes in alternative energy transfer systems [ 106 ]. Thus, in transgenic mouse models with an inhibited CK system, there is no clear correlation between the function of Mi-CK and the apparent K M ADP .…”

Section: Energy Transfer When Creatine Kinase Is Inhibited: Lessons F...mentioning

confidence: 99%

Ontogeny of cardiomyocytes: ultrastructure optimization to meet the demand for tight communication in excitation–contraction coupling and energy transfer

Birkedal

Laasmaa

Branovets

et al. 2022

Phil. Trans. R. Soc. B

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The ontogeny of the heart describes its development from the fetal to the adult stage. In newborn mammals, blood pressure and thus cardiac performance are relatively low. The cardiomyocytes are thin, and with a central core of mitochondria surrounded by a ring of myofilaments, while the sarcoplasmic reticulum (SR) is sparse. During development, as blood pressure and performance increase, the cardiomyocytes become more packed with structures involved in excitation–contraction (e-c) coupling (SR and myofilaments) and the generation of ATP (mitochondria) to fuel the contraction. In parallel, the e-c coupling relies increasingly on calcium fluxes through the SR, while metabolism relies increasingly on fatty acid oxidation. The development of transverse tubules and SR brings channels and transporters interacting via calcium closer to each other and is crucial for e-c coupling. However, for energy transfer, it may seem counterintuitive that the increased structural density restricts the overall ATP/ADP diffusion. In this review, we discuss how this is because of the organization of all these structures forming modules. Although the overall diffusion across modules is more restricted, the energy transfer within modules is fast. A few studies suggest that in failing hearts this modular design is disrupted, and this may compromise intracellular energy transfer. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

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Cardiac expression and location of hexokinase changes in a mouse model of pure creatine deficiency

Cited by 5 publications

References 84 publications

Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

Cardiomyocytes from female compared to male mice have larger ryanodine receptor clusters and higher calcium spark frequency

Ontogeny of cardiomyocytes: ultrastructure optimization to meet the demand for tight communication in excitation–contraction coupling and energy transfer

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