The most common disruption of circadian rhythms in modern society is the so-called social jetlag, i.e. the chronic mismatch between biological time (chronotype) and social time (e.g. waking up according to the alarm clock). However, it is not entirely clear whether social jetlag has any negative effects on health. A large study on a representative adult population of the Czech Republic, conducted by scientists from the Laboratory of Biological Rhythms of the Institute of Physiology of the CAS and published in the journal Sleep, revealed risk factors for the development of cardiovascular and metabolic diseases that are associated with an incorrect sleep schedule.
The authors of the study examined a unique population-representative dataset including 1957 blood samples of adults from across the Czech Republic with different daytime sleep patterns (chronotype). Nine biomarkers (cholesterol, blood lipids, glucose, cortisol, and others) were analyzed in the samples, and an association between social jetlag and biomarkers of cardio-metabolic health (total cholesterol and LDL levels) was found to be statistically significant, especially in people over 50 years of age. The authors also identified new factors influencing social jetlag in the study, such as commuting time to school or work or stress due to lack of time. The study also showed that flexible working hours effectively mitigate social jetlag.
Sládek M, Klusáček J, Hamplová D, Sumová A: Population-representative study reveals cardiovascular and metabolic disease biomarkers associated with misaligned sleep schedules. Sleep, Volume 46, Issue 6, June 2023, zsad037, IF: 5.6 DOI
How do the cells gain enough potassium? (17.5. 2023)
Potassium is an essential intracellular ion, and its optimum intracellular concentration is crucial for many processes; therefore it is fundamental for cells to regulate K+ uptake and efflux via specialised proteins precisely. The Trk1 protein is one of them. Using yeast cells, we showed that a very short part of the protein, the IL2 loop and its two conserved residues (serine 882 and threonine 900) are essential both for the proper folding of the nascent protein and for the regulation of the protein’s activity in response to changes in the extracellular concentration of potassium ions. The binding of regulatory proteins 14-3-3 to phosphorylated threonine 900 is crucial for this regulation.
14-3-3 proteins regulate the activity of Trk1 by binding to Thr900 in the second intracellular loop.
Masaryk J, Kale D, Pohl P, Ruiz-Castilla F, Zimmermannová O, Obšilová V, Ramos J, Sychrová H: The second intracellular loop of the yeast Trk1 potassium transporter is involved in regulation of activity, and interaction with 14–3-3 proteins. Computational and Structural Biotechnology Journal. 21 (2023), 2705-2716. ISSN 2001-0370. E-ISSN 2001-0370, IF: 6.155 DOI
Heat from skeletal muscle can protect not only against cold but also against obesity (27.2. 2023)
Heat production (thermogenesis) is essential for maintaining a constant body temperature, and is an important component of energy balance. Well-described mechanisms involved in heat generation include muscle shivering or non-shivering thermogenesis in brown adipose tissue. Thermogenesis in brown adipose tissue, which is dependent on the presence of the mitochondrial protein UCP1 (uncoupling protein 1), is the focus of interest for its potential use in the treatment of obesity. Other mechanisms of non-shivering thermogenesis and their significance are relatively poorly understood.
Scientists at the Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, investigated heat generation in two different strains of laboratory mice (C57BL/6J and A/J) that differ in their susceptibility to obesity. In C57BL/6J mice, obesity can be induced by a high-fat diet, whereas in A/J mice obesity does not occur under these conditions. Mice of both strains were able to acclimate to cold with only a small decrease in body temperature, initially using muscle shivering for thermogenesis. Prolonged exposure to cold led to activation of thermogenesis in brown adipose tissue in obesity-prone mice. Surprisingly, however, obesity-resistant mice failed to activate brown adipose tissue but increased non-shivering thermogenesis in skeletal muscle. Heat generation in muscle involved increased calcium ion cycling in the endoplasmic reticulum associated with higher mitochondrial oxidative activity.
The involvement of different thermogenic mechanisms could be related to the different susceptibility to obesity. The resistance of A/J mice to obesity is probably due to their ability to activate non-shivering thermogenesis in muscle. These results, published in Molecular Metabolism, also suggest a new possibility for obesity treatment by activating non-shivering thermogenesis in muscle. This is probably a more promising way to treat obesity than potential therapies based on increasing thermogenesis in brown adipose tissue. Especially because in the adult human, the capacity of skeletal muscle to burn fat energy stores is several fold greater than in brown adipose tissue. Thus, only a relatively small increase in thermogenesis in muscle could significantly reduce adipose tissue deposition. How to achieve such an increase is a challenge for further research
Janovska, P., P. Zouhar, K. Bardova, J. Otahal, M. Vrbacky, T. Mracek, K. Adamcova, L. Lenkova, J. Funda, T. Cajka, Z. Drahota, S. Stanic, A. C. Rustan, O. Horakova, J. Houstek, M. Rossmeisl and J. Kopecky (2023). „Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle.“ Mol Metab 69: 101683. IF = 8.568 DOI
Take a pill in the morning or in the evening? The mood stabilizer lithium affects the brain differently depending on the time of day (30.1. 2023)
Lithium is an effective mood stabilizer, but the mechanism of its therapeutic effect is not well understood. Prof. Sumová's team from the Institute of Physiology of the Czech Academy of Sciences investigated the effect of lithium on the circadian clock located in the ventricular barrier complex containing the choroid plexus, which is a part of the glymphatic system that influences gross brain function via the production of cerebrospinal fluid. They found that treating mice with lithium changed the level of clock gene expression in the choroid plexus. To study the effect of lithium in more detail, they used a transgenic mouse model with a circadian reporter (mPer2LUC) to monitor the choroid plexus clock in real time. When they applied the drug to tissue explanted from the mice in vitro, the effect on the clock was highly dependent on the timing of application. Lithium delayed the clock for most of the day, but during a short window it caused phase advances. Using specific inhibitors, the authors demonstrated that the effect was not mediated via inhibition of the enzyme GSK3, a canonical mechanism of lithium, but rather via modulation of PKC activity. The results suggest a novel mechanism of therapeutic action for lithium that aligns the function of the choroid plexus clock-related glymphatic system with the sleep-wake cycle to improve brain function in psychiatric patients. Importantly, the data argue for personalized timing of lithium treatment in patients with bipolar disorder.
Liška K, Dočkal T, Houdek P, Sládek M, Lužná V, Semenovykh K, Drapšin M, Sumová A: Lithium affects the circadian clock in the choroid plexus – A new role for an old mechanism, Biomedicine & Pharmacotherapy, Vol. 159, March 2023, 114292, IF 7.419 DOI
Heat or cold? New insights into the functioning of temperature-sensitive ion channels obtained in collaboration with Lund University (24.1. 2023)
Temperature-sensitive TRP ion channels are cellular molecular sensors involved in the transduction of sensory signals, pain perception (nociception) and the maintenance of ion homeostasis. Disturbances in their function are associated with many serious human diseases such as chronic pain, inflammation, cancer and various cardiovascular, neurological, respiratory, renal and metabolic disorders. The enormous hope of developing new drugs targeting these channels is greatly limited due to their intrinsic ability to be activated by stimuli of different modalities (polymodality), the mechanism of which has not yet been fully understood. An international team of scientists led by Prof. Peter M. Zygmund (Lund University, Malmö, Sweden), in collaboration with scientists from the Institute of Physiology of the Czech Academy of Sciences in Prague, has revealed two important mechanisms contributing to the polymodal regulation of TRP channels: The first study revealed the binding site and molecular nature of the binding of D9‑tetrahydrocannabiorcol (a natural plant cannabinoid with no psychotropic effects), which strongly facilitates the activation of TRPV2, thereby affecting the transmission of painful stimuli. The second study identified two separate specific regions that confer heat (> 35 °C) and cold (< 15 °C) sensitivity to a different receptor, TRPA1, and demonstrated that the temperature sensitivity of this receptor is critically dependent on oxidative and reducing environments. The results make an important contribution to the understanding of the general molecular mechanisms of chemical and thermal activation of TRP family channels and will find application in the search for possible approaches to their regulation by drugs.
Left panel: effect of cold (15°C) on activation of the human TRPA1 wild-type ion channel and a mutant in which the major amino acid residue C856 responsible for regulation by oxidizing and reducing agents is substituted for alanine. The channels were activated by a series of voltage pulses (from ‑160 mV to +200 mV). Right panel: visualization of the TRPA1 channel structure obtained by cryoelectron microscopy (PDB: 6v9w) as viewed from the side and top. Dynamic regions of the channel responsible for cold activation are highlighted in light blue. The position of cysteine C856 is shown in the detail of the structure of one subunit below.
Moparthi, L. - Sinica, Viktor - Moparthi, V. K. - Kreir, M. - Vignane, T. - Filipovic, M. R. - Vlachová, Viktorie - Zygmunt, P. M.The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain. Nature Communications. Roč. 13, č. 1 (2022), IF: 17.694 DOI
Zhang, L. - Simonsen, Ch. - Zímová, Lucie - Wang, K. - Moparthi, L. - Gaudet, R. - Ekoff, M. - Nilsson, G. - Hellmich, U. A. - Vlachová, Viktorie - Gourdon, P. - Zygmunt, P. M. Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function. Nature Communications. Roč. 13, č. 1 (2022), IF: 17.694, rok: 2021 DOI