Biology subjects

Popov, D. V.

Publications and source records attributed to Popov, D. V..

9 recordsLinked to original sources

bioRxiv2026

Bion-M 2 Biosatellite: Multisystem Mouse Responses to 30 Days in High-Latitude Orbit as a Deep-Space Analog

The combined effects of microgravity and deep-space radiation on whole-body physiology remain poorly quantified for future crewed missions. Bion-M 2, a 30-day high-latitude biosatellite carrying group-housed mice, achieved an ISS-comparable total dose with an enriched galactic cosmic ray fraction, approximating conditions beyond low-Earth orbit. A quantitative atlas of 73 physiological endpoints revealed pronounced antigravity muscle atrophy, immune and gastrointestinal remodeling, and delayed recovery of hematologic and visceral indices through 30 days post-landing. A dry-food-hydrogel diet transformed this response into a stress-dominated, densely interconnected physiological state. Pharmacological Nrf2 activation with omaveloxolone preserved hindlimb muscle mass at ground-control levels and protected visceral organs. These findings establish a systems-level baseline for mammalian adaptation to a deep-space-analog orbit and identify diet and Nrf2 activation as tractable countermeasure levers.

systems biology↗

bioRxiv2025

Different effects of 3-week disuse on the phenotype and gene expression of the calf and thigh muscles

Disuse, like several other pathological conditions, has specific effects on various skeletal muscles; the mechanisms underlying these responses remain unclear. We aimed to compare the disuse-induced changes in the phenotype and proteome of the calf and thigh muscles, and to assess the extent to which these proteomic changes are regulated at the mRNA and other levels. Twelve healthy young males participated in 3-week bed rest. Disuse resulted in a greater decrease in lean mass, aerobic performance, and changes in the proteome and transcriptome of the calf muscles/m. soleus than the thigh muscles/m. vastus lateralis. A greater decrease in calf muscle mass was associated with a decrease in the expression/deactivation of translation regulators, but not to the expression of the main sarcomeric proteins. At the same time, a significant decrease in aerobic performance of the ankle plantar flexors occurred without changing the expression of oxidative enzymes - a marker of mitochondrial density. That decrease was associated with dysregulation of mitochondrial biogenesis. Most large-scale changes in the transcriptome did not translate into changes in the proteome, indicating post-transcription protein buffering. However, changes in the RNA levels were revealed to play a dominant role in regulating specific proteins, whereas for others, this factor played little or no role. In conclusion, our findings partially explain why calf muscles with a strong postural function are more sensitive to short-term disuse. This provides a foundation for developing targeted approaches to counteract the negative effects of disuse on different muscles.

physiology↗

bioRxiv2024

Transcription factors associated with regulation of transcriptome in human thigh and calf muscles at baseline and after one week of disuse

Disuse has a negative impact on the postural muscles of the trunk and legs. Different leg muscles demonstrate a differentiated and conservative response to disuse, in terms of a decrease in muscle mass, strength, aerobic performance, and changes in gene expression. We aimed to identify transcription factors regulating gene expression at baseline and after disuse in human m. soleus - a "slow" muscle with a strong postural function, and "mixed" m. vastus lateralis. Biopsies were taken from these muscles prior to and after 6 days of strict disuse (dry immersion). The enriched transcription factor binding sites (and corresponding factors) in the individual promoter regions of co-expressed genes were examined using the positional weight matrix approach. The baseline transcriptomic profiles and the disuse-induced changes (RNA-seq) differ significantly between muscles. In particular, the specific and significant response to disuse in m. soleus was found to be strongly related to the suppression of genes regulating the mitochondrial energy metabolism, the activation of the inflammatory response and the ubiquitin-proteasome system. This response is associated with the proinflammatory transcription factors such as families IRF, STAT, and other. The validity of approximately two-thirds of the predicted transcription factors was indirectly confirmed by the analysis of their function described in the literature. These identified transcription factors appear to be promising candidates for future targeted studies that mechanistically investigate gene expression regulation in various muscles at baseline, following disuse or inactivity. HighlightsO_LIDisuse has a different negative impact on the different human postural leg muscles. C_LIO_LIThe transcriptome regulation in m. soleus and m. vastus lateralis differs markedly. C_LIO_LIThe gene response to disuse in m. soleus is greater than in m. vastus lateralis. C_LIO_LIThis partially related to activation of inflammation-induced transcription factors. C_LI

physiology↗

bioRxiv2024

Multidirectional effect of low-intensity electrical myostimulation on gene expression and phenotype in thigh and calf muscles after one week of disuse

PurposeThis study investigated the effects of a one-week disuse, both with and without low-intensity neuromuscular electrical stimulation - a safe (non-traumatic) approach to prevent the loss of muscle mass, on the functional capacities and gene expression in thigh and calf muscles. MethodsThis study assessed the efficiency of low-intensity ([~]10% of maximal voluntary contraction) electrical stimulation in preventing the negative effects of 7-day disuse (dry immersion without and with daily stimulation) on the strength and aerobic performance of the ankle plantar flexors and knee extensors, mitochondrial function in permeabilized muscle fibers, and the proteomic (quantitative mass spectrometry-based analysis) and transcriptomic (RNA-sequencing) profiles of the soleus muscle and vastus lateralis muscle. ResultsApplication of electrical stimulation during dry immersion prevented a decrease in the maximal strength and a slight reduction in aerobic performance of the knee extensors, as well as a decrease in maximal (intrinsic) ADP-stimulated mitochondrial respiration and changes in the expression of genes encoding mitochondrial, extracellular matrix, and membrane proteins in the vastus lateralis muscle. In contrast, for the ankle plantar flexors/soleus muscle, electrical stimulation had a positive effect only on maximal mitochondrial respiration, but slightly accelerated the decline in the maximal strength and muscle fiber cross-sectional area, which appears to be related to the activation of inflammatory genes. ConclusionThe data obtained open up broad prospects for the use of low-intensity electrical stimulation to prevent the negative effects of disuse for "mixed" muscles, meanwhile, the optimization of the stimulation protocol is required for "slow" muscles. Practitioner PointsO_LILow-intensity electrical myostimulation is often used as an alternative to exercise and high-intensity electrical stimulation to prevent the loss of muscle mass and function in patients with severe chronic diseases and in spaceflight. However, its effect on muscles with different functional capacities remains uncertain. C_LIO_LIOne week of disuse (dry immersion) lead to a comparable decrease in the maximal strength and (intrinsic) mitochondrial respiration in both the ankle plantar flexors/soleus muscle and the knee extensors/vastus lateralis muscle. Meanwhile changes in gene expression (transcriptome) were three times more pronounced in the soleus muscle than in the vastus lateralis muscle. C_LIO_LIApplication of electrical stimulation during disuse prevented most of the negative effects of disuse in the knee extensors/vastus lateralis muscle, but accelerated the decline in the maximal strength/muscle fiber cross-sectional area in the ankle plantar flexors/soleus muscle, which may be related to the activation of genes regulating the inflammatory response. C_LI

physiology↗

bioRxiv2023

Age-related changes in human skeletal muscle transcriptome and proteome are moreaffected by chronic inflammation and physical inactivity than primary aging

Evaluation of the influence of primary and secondary aging on the manifestation of molecular and cellular hallmarks of aging is a challenging and currently unresolved issue. Our study represents the first demonstration of the distinct role of primary aging and chronic inflammation/physical inactivity - the most important drivers of secondary aging, in the regulation of transcriptomic and proteomic profiles in human skeletal muscle. To achieve this purpose, young healthy people (n=15), young (n=8) and older (n=37) patients with knee/hip osteoarthritis, a model to study the effect of long-term inactivity and chronic inflammation on the vastus lateralis muscle, were included in the study. It was revealed that widespread and substantial age-related changes in gene expression in older patients relative to young healthy people ([~]4,000 genes regulating mitochondrial function, proteostasis, cell membrane, secretory and immune response) were related to the long-term physical inactivity and chronic inflammation rather than primary aging. Primary aging contributed mainly to the regulation of genes ([~]200) encoding nuclear proteins (regulators of DNA repair, RNA processing, and transcription), mitochondrial proteins (genes encoding respiratory enzymes, mitochondrial complex assembly factors, regulators of cristae formation and mitochondrial reactive oxygen species production), as well as regulators of proteostasis. It was found that proteins associated with aging were regulated mainly at the post-transcriptional level. The set of putative primary aging genes and their potential transcriptional regulators can be used as a resource for further targeted studies investigating the role of individual genes and related transcription factors in the emergence of a senescent cell phenotype.

physiology↗

bioRxiv2023

Knockout of Hsp70 genes significantly affects locomotion speed and gene expression in leg skeletal muscles of Drosophila melanogaster

The functions of the Hsp70 genes were studied using a line of D. melanogaster with knockout of six these genes out of thirteen. Namely, effect of knockout of Hsp70 genes on negative geotaxis climbing (locomotor) speed and the ability to adapt to climbing training (0.5-1.5 h/day, 7 days/week, 19 days) were examined. Seven- and 23-day-old Hsp70- flies demonstrated a comparable reduction (2-fold) in locomotor speed and widespread changes in leg skeletal muscle transcriptome (RNA-seq), compared to w1118flies. To identify the functions of genes related to decreased locomotor speed the overlapped differentially expressed genes at both time points were analyzed: the up-regulated genes encoded extracellular proteins, regulators of drug metabolism and antioxidant response, while down-regulated genes encoded regulators of carbohydrate metabolism and transmembrane proteins. Additionally, in Hsp70- flies, activation of transcription factors related to disruption of the fibril structure and heat shock response (Hsf) were predicted, using the position weight matrix approach. In the control flies, adaptation to chronic exercise training was associated mainly with gene response to a single exercise bout, while the predicted transcription factors were related to stress/immune (Hsf, NF-kB, etc.) and early gene response. In contrast, Hsp70- flies demonstrated no adaptation to training, as well as significantly impaired gene response to a single exercise bout. In conclusion, the knockout of Hsp70 genes not only reduced physical performance, but also disrupted adaptation to chronic physical training, which is associated with changes in leg skeletal muscle transcriptome and impaired gene response to a single exercise bout. New & NoteworthyO_LIKnockout of six Hsp70 genes in D. melanogaster reduced locomotion (climbing) speed that is associated with genotype-specific differences in leg skeletal muscle gene expression. C_LIO_LIDisrupted adaptation of Hsp70- flies to chronic exercise training is associated with impaired gene response to a single exercise bout. C_LI

physiology↗

bioRxiv2021

A model of exercise-induced changes in metabolism, signaling, and gene expression in skeletal muscle

Skeletal muscle is the principal contributor to exercise-induced changes in human metabolism. Strikingly, although it has been demonstrated that a lot of metabolites accumulating in blood and human skeletal muscle during an exercise activate different signaling pathways and induce expression of many genes in working muscle fibres, the system understanding of signaling-metabolic pathways interrelations with downstream genetic regulation in the skeletal muscle is still elusive. Herein, a physiologically based computational model of skeletal muscle comprising energy metabolism, Ca2+ and AMPK signalling pathways, and expression regulation of genes with early and delayed responses has been developed based on a modular modeling approach. The integrated modular model validated on diverse including original experimental data and different exercise modes provides a comprehensive in silico platform in order to decipher and track cause-effect relationships between metabolic, signaling and gene expression levels in the skeletal muscle.

systems biology↗

bioRxiv2019

DNA methylation across the genome in aged human skeletal muscle tissue and muscle stem cells: The role of HOX genes and physical activity

Skeletal muscle tissue demonstrates global hypermethylation with aging. However, methylome changes across the time-course of differentiation in aged human muscle derived stem cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 {+/-} 4.4 years) and aged (83 {+/-} 4 years) human skeletal muscle and that of young/aged muscle stem cells over several time points of differentiation (0, 72 hours, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged muscle stem cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alteration in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in the focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and isolated muscle stem cells, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle and tissue and stem cells (on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P). Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and muscle stem cells and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

physiology↗

bioRxiv2019

UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

We aimed to investigate a novel and uncharacterised E3 ubiquitin ligase in skeletal muscle atrophy, recovery from atrophy/injury, anabolism and hypertrophy. We demonstrated an alternate gene expression profile for UBR5 versus well characterised E3-ligases, MuRF1/MAFbx, where after atrophy evoked by continuous-low-frequency electrical-stimulation in rats, MuRF1/MAFbx were both elevated yet UBR5 was unchanged. Furthermore, after recovery of muscle mass post tetrodotoxin (TTX) induced-atrophy in rats, UBR5 was hypomethylated and increased at the gene expression level, while a suppression of MuRF1/MAFbx was observed. At the protein level, we also demonstrated a significant increase in UBR5 after recovery of muscle mass from hindlimb unloading in both adult and aged rats, and after recovery from atrophy evoked by nerve crush injury in mice. During anabolism and hypertrophy, UBR5 gene expression increased following acute loading in three-dimensional bioengineered mouse muscle in-vitro, and after chronic electrical-stimulation-induced hypertrophy in rats in-vivo, without increases in MuRF1/MAFbx. Additionally, UBR5 protein abundance increased following functional overload-induced hypertrophy of the plantaris muscle in mice and during differentiation of primary human muscle cells. Finally, in humans, genetic association studies (>700,000 SNPs) demonstrated that the A alleles of rs10505025 and rs4734621 SNPs in the UBR5 gene were strongly associated with larger cross-sectional area of fast-twitch muscle fibres and favoured strength/power versus endurance/untrained phenotypes. Overall, we suggest that UBR5 is a novel E3 ubiquitin ligase that is inversely regulated to MuRF1/MAFbx, is epigenetically regulated, and is elevated at both the gene expression and protein level during recovery from skeletal muscle atrophy and hypertrophy.\n\nKey PointsO_LIWe have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, is altered epigenetically (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression is positively correlated with increasing lean leg mass after training and retraining.\nC_LIO_LIIn the present study we extensively investigate this novel and uncharacterised E3 ubiquitin ligase (UBR5) in skeletal muscle atrophy, recovery from atrophy and injury, anabolism and hypertrophy.\nC_LIO_LIWe demonstrated that UBR5 was epigenetically via altered DNA methylation during recovery from atrophy.\nC_LIO_LIWe also determined that UBR5 was alternatively regulated versus well characterised E3 ligases, MuRF1/MAFbx, at the gene expression level during atrophy, recovery from atrophy and hypertrophy.\nC_LIO_LIUBR5 also increased at the protein level during recovery from atrophy and injury, hypertrophy and during human muscle cell differentiation.\nC_LIO_LIFinally, in humans, genetic variations of the UBR5 gene were strongly associated with larger fast-twitch muscle fibres and strength/power performance versus endurance/untrained phenotypes.\nC_LI

physiology↗