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

Martin Laasmaa, Jelena Branovets, Karina Barsunova, Niina Karro, Craig A Lygate, Rikke Birkedal, Marko Vendelin Am J Physiol Heart Circ Physiol. 2021 Feb 1;320(2):H805-H825 PMID: 33275525DOI: 10.1152/ajpheart.00300.2020 Abstract The creatine kinase system facilitates energy transfer between mitochondria and the major ATPases in the heart. Creatine-deficient mice, which lack arginine-glycine amidinotransferase (AGAT) to synthesize creatine and homoarginine, exhibit reduced cardiac co...
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Cardiac expression and location of hexokinase changes in a mouse model of pure creatine deficiency

Jelena Branovets, Niina Karro, Karina Barsunova, Martin Laasmaa, Craig A Lygate, Marko Vendelin, Rikke Birkedal Am J Physiol Heart Circ Physiol. 2021 Feb 1;320(2):H613-H629 PMID: 33337958DOI: 10.1152/ajpheart.00188.2020 Abstract Creatine kinase (CK) is considered the main phosphotransfer system in the heart, important for overcoming diffusion restrictions and regulating mitochondrial respiration. It is substrate limited in creatine-deficient mice lacking l-arginine:glycine amidinotr...
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IOCBIO Kinetics: An open-source software solution for analysis of data traces

Marko Vendelin, Martin Laasmaa, Mari Kalda, Jelena Branovets, Niina Karro, Karina Barsunova, Rikke Birkedal PLoS Comput Biol. 2020 Dec 22;16(12):e1008475. PMID: 33351800PMCID: PMC7787677DOI: 10.1371/journal.pcbi.1008475 Abstract Biological measurements frequently involve measuring parameters as a function of time, space, or frequency. Later, during the analysis phase of the study, the researcher splits the recorded data trace into smaller sections, analyzes each section separately b...
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Marker enzyme activities in hindleg from creatine-deficient AGAT and GAMT KO mice – differences between models, muscles, and sexes

Barsunova K, Vendelin M, Birkedal R Sci Rep 2020 May;10(1):7956 PMID: 32409787 Abstract Creatine kinase (CK) functions as an energy buffer in muscles. Its substrate, creatine, is generated by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). Creatine deficiency has more severe consequences for AGAT than GAMT KO mice. In the present study, to characterize their muscle phenotype further, we recorded the weight of tibialis anterior (TA), extensor digi...
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Cardiac muscle regulatory units are predicted to interact stronger than neighboring cross-bridges

Kalda M, Vendelin M Sci Rep 2020 Mar;10(1):5530 PMID: 32218497 Full text: https://doi.org/10.1038/s41598-020-62452-7 Abstract Model simulations (top) and the scheme showing cooperativity modes Strong interactions between cross-bridges (XB) and regulatory units (RU) lead to a steep response of cardiac muscle to an increase in intracellular calcium. We developed a model to quantitatively assess the influence of different types of interactions within the sarcomere on the prope...
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Energy-efficiency of Cardiomyocyte Stimulation with Rectangular Pulses

Laasmaa M, Lu P, Veletić M, Louch WE, Bergsland J, Balasingham I, Vendelin M Sci Rep 2019 Sep;9(1):13307 PMID: 31527628 Abstract In cardiac pacemaker design, energy expenditure is an important issue. This work aims to explore whether varying stimulation pulse configuration is a viable optimization strategy for reducing energy consumption by the pacemaker. A single cardiomyocyte was used as an experimental model. Each cardiomyocyte was stimulated with different stimulation protocols using rec...
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Respiration of permeabilized cardiomyocytes from mice: no sex differences, but substrate-dependent changes in the apparent ADP-affinity

Karro N, Laasmaa M, Vendelin M, Birkedal R Sci Rep 2019 Aug;9(1):12592 PMID: 31467353 Abstract Sex differences in cardiac physiology are getting increased attention. This study assessed whether isolated, permeabilized cardiomyocytes from male and female C57BL/6 mice differ in terms of their respiration with multiple substrates and overall intracellular diffusion restriction estimated by the apparent ADP-affinity of respiration. Using respirometry, we recorded 1) the activities of respiratory...
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IOCBIO Sparks detection and analysis software

Laasmaa M, Karro N, Birkedal R, Vendelin M. PeerJ. 2019 Mar 29;7:e6652 PMID: 30956900 Full text: https://doi.org/10.7717/peerj.6652 Abstract Analysis of calcium sparks in cardiomyocytes can provide valuable information about functional changes of calcium handling in health and disease. As a part of the calcium sparks analysis, sparks detection and characterization is necessary. Here, we describe a new open-source platform for automatic calcium sparks detection from line ...
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Revealing calcium fluxes by analyzing inhibition dynamics in action potential clamp

Laasmaa M, Birkedal R, Vendelin M J. Mol. Cell. Cardiol. Volume 100, November 2016, Pages 93–108 PMID: 27702573 Full text: http://doi.org/10.1016/j.yjmcc.2016.08.015 Abstract In cardiac excitation-contraction coupling (ECC), calcium enters the cytosol via L-type Ca2+ channels (LTCC) and reverse Na+/Ca2+-exchange (NCXrev), or is released from the sarcoplasmic reticulum (SR) by Ca2+-induced Ca2+-release (CICR). The magnitude of Ca2+ influx via the different pathways varies with the ...
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Metabolic compartmentation in rainbow trout cardiomyocytes: coupling of hexokinase but not creatine kinase to mitochondrial respiration

Karro N, Sepp M, Jugai S, Laasmaa M, Vendelin M, Birkedal R J. Comp. Physiol. B, Biochem. Syst. Environ. Physiol. 2016 Aug; PMID: 27522222 Full text: http://doi.org/10.1007/s00360-016-1025-x Abstract Rainbow trout (Oncorhynchus mykiss) cardiomyocytes have a simple morphology with fewer membrane structures such as sarcoplasmic reticulum and t-tubules penetrating the cytosol. Despite this, intracellular ADP diffusion is restricted. Intriguingly, although diffusion is restricted, trout cardiom...
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