Biology subjects

Frolov, M. V.

Publications and source records attributed to Frolov, M. V..

7 recordsLinked to original sources

bioRxiv2026

Arginine Kinase 1 regulates energy homeostasis in Drosophila muscle development

In Drosophila, Arginine kinase 1 (Argk1) is involved in maintaining ATP homeostasis during bursts of activity in tissues with high and variable rates of energy turnover such as muscle. However, its role beyond stress conditions is less understood. Here, we show that Argk1 maintains energy homeostasis during flight muscle development and is required for animal viability and proper muscle function. The knockdown of Argk1 causes defects in both early and late stages of myogenesis. In the proliferating myoblasts associated with the wing disc, Argk1 depletion results in a reduction in cell size without changes in cell cycle progression. Single cell RNA-sequencing revealed that the overall composition of differentiating and undifferentiating myoblasts is not altered. Nonetheless, Argk1 knockdown causes broad alterations in the expression of genes involved in various metabolic pathways. This correlates with low levels in both ATP content and NAD+/NADH ratio. Later in muscle development, Argk1-depleted muscles completely lack spontaneous muscle contractions that are essential in myofibrillogenesis. Accordingly, Argk1 knockdown results in severe defects in sarcomere structure, while the mitochondrial network is highly fragmented. Furthermore, muscle growth is severely reduced. Thus, our data reveal an essential role for Argk1 in maintaining energy homeostasis throughout muscle development, which is required to meet the demand to support myofibrillogenesis, muscle growth and proper muscle function.

developmental biology↗

bioRxiv2025

Medium-Chain Fatty Acid exposure in non-transformed mammary glands leads to pro-tumorigenic alterations associated with aging

The local breast environment is a valuable research focus for identifying the etiological and biological factors that contribute to the development of breast cancer. Single-cell RNA sequencing shows that the increased availability of the medium-chain fatty acid octanoic acid induces changes typical of the aged mammary gland, including downregulation of cell-cell junctions, altered extracellular matrix (ECM)-receptor interactions, and upregulation of aging markers like MDK and GDF15. Ex vivo exposure to medium-chain fatty acids compromises cell-cell junctions leading to cell dissemination. As aging is associated with an increased risk of developing breast cancer, it is crucial to identify the factors driving these age-related changes in the mammary gland to develop effective cancer prevention strategies. Given that the proportion of breast adipocytes increases with age, we propose that the remodeling of the mammary gland associated with aging is partly due to the increase in adipocytes and fatty-acid release.

cancer biology↗

bioRxiv2024

Metabolic shift to serine pathway induced by lipids confers oncogenic properties in non-transformed breast cells

A lipid metabolism gene signature is associated with the risk of estrogen negative breast cancer (ER-BC). In vitro, lipid exposure alters histone methylation affecting gene expression and increasing flux through various metabolic reactions; but little is known about the mechanism(s) linking lipids and epigenetic reprogramming with the genesis of ER-BC. Here we show that the metabolism of the medium-chain fatty acid Octanoic Acid (OA) in preference to glucose and glutamine results in a metabolic shift toward the serine pathway increasing the production of SAM, glutathione, and 2-HG, with implications for oncogenesis: SAM production results in epigenetic fostered plasticity leading to reprogramming/selecting cells that express Neural, EMT and BC related genes. 2-HG exposure results in appearance of DNA breaks, potentially consequent to the inhibition of essential demethylases for HR repair. ROS increases shortly after OA exposure and is mitigated by antioxidant defenses, which favors/enables the survival of specific cell subtypes.

cancer biology↗

bioRxiv2023

The RU486-dependent activation of the GeneSwitch system in adult muscles leads to severe adverse effects in Drosophila

Robust genetic systems to control the expression of transgenes in a spatial and temporal manner are a valuable asset for researchers. The GeneSwitch system induced by the drug RU486 has gained widespread use in the Drosophila community. However, some concerns were raised as negative effects were seen depending on the stock, transgene, stage and tissue under study. Here, we characterized the adverse effects triggered by activating the GeneSwitch system in adult muscles using the MHC-GS-GAL4 driver. When a control, mock UAS-RNAi transgene was induced by feeding adult flies with RU486, we found that the overall muscle structure, including myofibrils and mitochondrial shape, was significantly disrupted and led to a significant reduction in the lifespan. Remarkably, lifespan was even shorter when two copies of the driver were used even without the mock UAS-RNAi transgene. Thus, researchers should be cautious when interpreting the results given the adverse effects we found when inducing RU486-dependent MHC-GS-GAL4 in adult muscles. To counter the impact of these effects we recommend setting up additional control groups, such as a mock UAS-RNAi transgene, to validate the findings when using this inducible genetic system, as comparing the phenotypes between RU486-treated and untreated animals could be insufficient.

genetics↗

bioRxiv2022

The binding sites of E2F transcription factor in Drosophila metabolic genes are functionally distinct

The canonical role of the transcription factor E2F is to control the expression of cell cycle genes by binding to the E2F sites in their promoters. However, the list of putative E2F target genes is extensive and includes many metabolic genes, yet the significance of E2F in controlling expression of these genes remains largely unknown. Here, we used the CRISPR/Cas9 technology to introduce point mutations in the E2F sites upstream of five endogenous metabolic genes in Drosophila. We found that the impact of these mutations on both the recruitment of E2F and the expression of the target genes varied, with the glycolytic gene, Phosphoglycerate kinase (Pgk), being mostly affected. The loss of E2F regulation on Pgk gene led to a decrease in glycolytic flux, TCA cycle intermediates levels, ATP content and an abnormal mitochondrial morphology. Remarkably, chromatin accessibility was significantly reduced at multiple genomic regions in Pgk{Delta}E2F mutants. These regions contained hundreds of genes, including metabolic genes that were downregulated in Pgk{Delta}E2F mutants. Moreover, Pgk{Delta}E2F animals had shortened life span and exhibited defects in high-energy consuming organs, such as ovaries and muscles. Collectively, our results illustrate how the pleiotropic effects on metabolism, gene expression and development in the Pgk{Delta}E2F animals underscore the importance of E2F regulation on a single E2F target, Pgk.

developmental biology↗

bioRxiv2021

E2F/Dp inactivation in fat body cells triggers systemic metabolic changes

The E2F transcription factors play a critical role in controlling cell fate. In Drosophila, the inactivation of E2F in either muscle or fat body results in lethality, suggesting an essential function for E2F in these tissues. However, the cellular and organismal consequences of inactivating E2F in these tissues are not fully understood. Here, we show that the E2F loss exerts both tissue-intrinsic and systemic effects. The proteomic profiling of E2F-deficient muscle and fat body revealed that E2F regulates carbohydrate metabolism, a conclusion further supported by metabolomic profiling. Intriguingly, animals with E2F-deficient fat body had a lower level of circulating trehalose and reduced storage of fat. Strikingly, a sugar supplement was sufficient to restore both trehalose and fat levels, and subsequently, rescued animal lethality. Collectively, our data highlight the unexpected complexity of E2F mutant phenotype, which is a result of combining both tissue-specific and systemic changes that contribute to animal development.

developmental biology↗

bioRxiv2020

Cell autonomous versus systemic Akt isoform deletions uncovered new roles for Akt1 and Akt2 in breast cancer

Studies in three mouse models of breast cancer identified profound discrepancies between cell autonomous and systemic Akt1 or Akt2 deletion on breast cancer tumorigenesis and metastasis. First, unlike systemic Akt1 deletion, which inhibits metastasis, cell autonomous Akt1 deletion does not. Second, systemic Akt2 deletion does not inhibit mammary tumorigenesis and metastasis, but cell autonomous Akt2 deletion eliminates ErbB2 expressing cells in the mammary gland and prevents tumorigenesis. However, the elevation in insulin by Akt2 systemic deletion hyperactivates tumor Akt, enabling ErbB2 expression, and exacerbates mammary tumorigenesis. Decreasing insulin level inhibits accelerated tumorigenesis by systemic Akt2 deletion. Single cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing the survival and mobilization of tumor-associated neutrophils. Importantly, neutrophil-specific deletion of Akt1 is sufficient to exert resistance to metastasis. The results underscore the importance of determining systemic effects rather than cell autonomous effects as a proof of concept for cancer therapy.

cancer biology↗