Altered calcium handling in cardiomyocytes from arginine-glycine amidinotransferase-knockout mice is rescued by creatine

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

doi:10.1152/ajpheart.00300.2020

Cited by 6 publications

(46 citation statements)

References 65 publications

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“…(2002), while the LTCC current–voltage relationship did not show a statistically significant difference between sexes, mean current density was larger in females than in males under control conditions, in agreement with our data (Laasmaa et al., 2021). LTCC current decay, found in our earlier work (Laasmaa et al., 2021), was faster in females than in males ( P = 0.04) under control conditions, with ISO reducing the decay similarly for both sexes (no statistically significant interactions between sex and ISO treatment when analysed by ANOVA). In other studies, no statistically significant difference in LTCC current decay was observed (Grandy & Howlett, 2006; Parks et al., 2014).…”

Section: Discussionsupporting

confidence: 92%

“…While we earlier did not find any statistically significant difference between sexes in L‐type calcium channel (LTCC) and sarco/endoplasmic reticulum Ca 2+ ‐ATPase (SERCA) expression (Laasmaa et al., 2021), we looked into the regulatory effect imposed by phospholamban, PLB and/or its phosphorylation on Ser16 (PKA phosphorylation) or Thr17 (CaMKII phosphorylation). We found that the expression of PLB and its phosphorylated forms was not statistically significantly different between sexes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the current work context, for comparison with earlier electrophysiological studies on sex difference, we reanalysed the dataset from Laasmaa et al. (2021) using only wild‐type mice. According to our earlier data on Ca 2+ transients obtained using patch clamp stimulated cardiomyocytes, the Ca 2+ transient amplitude was not statistically significantly different between female and male cardiomyocytes under control conditions.…”

Section: Discussionmentioning

confidence: 99%

“…We also analysed the LTCC current from our earlier study (Laasmaa et al., 2021). At the ion channel level, the maximal LTCC current was larger in females than in males ( P = 0.02) under control conditions.…”

Section: Discussionmentioning

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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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

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show abstract

“…Likewise, Faller and co-workers have shown that impaired cardiac contractile function in Agat −/− mice is rescued by hArg, but not creatine (Faller et al, 2018). By contrast, Laasmaa et al showed that impaired calcium handling by isolated cardiomyocytes from Agat −/− mice is normalized by creatine supplementation when creatine is supplemented from weaning (Laasmaa et al, 2021). Taken together, these data suggest that hArg and creatine play differential roles in mediating the pathophysiological phenotypes of Agat −/− mice, which are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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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Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

Birkedal,

Branovets,

Vendelin

2024

FEBS Letters

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Intracellular molecules are transported by motor proteins or move by diffusion resulting from random molecular motion. Cardiomyocytes are packed with structures that are crucial for function, but also confine the diffusional spaces, providing cells with a means to control diffusion. They form compartments in which local concentrations are different from the overall, average concentrations. For example, calcium and cyclic AMP are highly compartmentalized, allowing these versatile second messengers to send different signals depending on their location. In energetic compartmentalization, the ratios of AMP and ADP to ATP are different from the average ratios. This is important for the performance of ATPases fuelling cardiac excitation‐contraction coupling and mechanical work. A recent study suggested that compartmentalization modulates the activity of creatine kinase and adenylate kinase in situ. This could have implications for energetic signaling through, for example, AMP‐activated kinase. It highlights the importance of taking compartmentalization into account in our interpretation of cellular physiology and developing methods to assess local concentrations of AMP and ADP to enhance our understanding of compartmentalization in different cell types.

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Altered calcium handling in cardiomyocytes from arginine-glycine amidinotransferase-knockout mice is rescued by creatine

Cited by 6 publications

References 65 publications

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

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

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

Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

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